[Objectives]To explore the synthetic process of PD-L1 small molecule inhibitors,focusing on optimizing key reaction conditions and synthetic routes.[Methods]By analyzing the pharmacophore design of PD-L1 small molecul...[Objectives]To explore the synthetic process of PD-L1 small molecule inhibitors,focusing on optimizing key reaction conditions and synthetic routes.[Methods]By analyzing the pharmacophore design of PD-L1 small molecule inhibitors and combining the optimization of synthetic methods and the improvement of reaction conditions,an efficient synthetic process was developed.[Results]Through optimization of reaction conditions,not only were the purity and yield of the products improved,but the inhibitory activity of the compounds was also significantly enhanced.Some compounds demonstrated strong anti-tumor effects in both in vitro and in vivo models.[Conclusions]This study aims to provide theoretical support and technical guidance for the efficient synthesis of small molecule inhibitors,offering new ideas and practical foundations for drug development in tumor immunotherapy.展开更多
This paper analyzes challenges encountered during the scale-up production of small molecule inhibitors,focusing on synthesis efficiency,solubility/bioavailability,quality control,stability/storage,and side effect pred...This paper analyzes challenges encountered during the scale-up production of small molecule inhibitors,focusing on synthesis efficiency,solubility/bioavailability,quality control,stability/storage,and side effect prediction/control.To address these issues,targeted solutions leveraging modern technologies are proposed and implemented:synthesis efficiency and purity were significantly enhanced through process optimization,green chemistry principles,and efficient catalysts;solubility and bioavailability were improved utilizing solid dispersion and nano-crystal technologies;process scale-up was optimized with online monitoring systems and continuous flow chemistry,ensuring product quality consistency;computer-aided drug design(CADD)was employed to predict and mitigate potential side effects.These integrated approaches effectively addressed key bottlenecks in the industrial-scale manufacturing of small molecule inhibitors.展开更多
The RAS/mitogen-activated protein kinase(MAPK)pathway disorder induced by the missense mutations in the tyrosine-protein phosphatase non-receptor type 11(PTPN11)gene which resulted in the nonreceptor protein tyrosine ...The RAS/mitogen-activated protein kinase(MAPK)pathway disorder induced by the missense mutations in the tyrosine-protein phosphatase non-receptor type 11(PTPN11)gene which resulted in the nonreceptor protein tyrosine phosphatase SHP2 dysfunction has been reported in many lung cancer cases.Moreover,the Src homology region 2(SH2)-containing protein tyrosine phosphatase 2(SHP2)mutation or deletion triggers multiple signaling pathway dysfunctions including RAS/MAPK,RAS/extracellular-signal-regulated kinase(ERK),phosphatidylinositol 3-kinase(PI3K)/protein kinase B(AKT),Janus kinase/signal transducers and activators of transcription(JAK/STAT)and Hippo/yes-associated protein(YAP)which affect the expression of growth factors,cytokines and hormones.In recent years,the developing of the small molecule SHP2 inhibitors received a lot of attention.In this review,we summarize the recent years'progresses of the SHP2 inhibitors development for the lung cancer treatment.展开更多
Signal transducer and activator of transcription 3(STAT3)is a member of the transcription factors involved in regulating many physiological and pathological processes,such as cell proliferation,angiogenesis and immune...Signal transducer and activator of transcription 3(STAT3)is a member of the transcription factors involved in regulating many physiological and pathological processes,such as cell proliferation,angiogenesis and immune escape.STAT3 has been identified as a potential therapeutic target for various cancers.Although numerous STAT3 inhibitors have been discovered and optimized to directly inhibit STAT3 activity,they are not yet authorized for clinical use and only a few have entered clinical trials.Furthermore,several proteolysis-targeting chimera(PROTAC)molecules with STAT3 degrading effects have been developed.The event-driven action of PROTAC overcome the drawbacks of STAT3,a traditional undruggable target,and addressed possible resistance to small-molecule inhibitors by degrading the entire STAT3 protein.In this review,we presented a brief introduction to STAT3 and its functions in various cancers,and systematically overviewed the pharmacological effects of inhibitors targeting different domains of STAT3 in the last three years,the structural characterization of the main scaffold,the design strategies,and the pharmacological activities of the substituents.Also,the binding patterns and interactions of some inhibitors with STAT3 were analyzed in detail and the recent advances in STAT3 degraders are also summarized.We anticipate that this perspective will contribute to the design and optimize more novel effective and specific STAT3 inhibitors or degraders for carcinoma treatment.展开更多
An increasing amount of evidence shows that type I interferon response,which is induced by cyclic guanosine monophosphate-adenosine monophosphate synthase(cGAS)and stimulator of interferon genes(STING)is closely assoc...An increasing amount of evidence shows that type I interferon response,which is induced by cyclic guanosine monophosphate-adenosine monophosphate synthase(cGAS)and stimulator of interferon genes(STING)is closely associated with health and neuroinflammatory diseases.Abnormal activation or loss of control of the cGAS-STING axis affects the development of neuroinflammation.Thus,we examined its role in major neurological diseases,including traumatic brain injury,Alzheimer’s disease,Parkinson’s disease,Huntington’s disease,multiple sclerosis,herpes simplex encephalitis,and ataxia-telangiectasia.Additionally,targeted intervention of the cGAS-STING axis to control neuroinflammation and treat related diseases has become the focus of current clinical research.This article describes the development of cGAS inhibitors and small molecules that target the cGAS-STING axis and explores the potential applications of STING inhibitors and agonists in clinical research.In summary,the cGAS-STING axis may impact neurological diseases more than a single protein or gene.Future studies should focus on elucidating the functional dynamics and regulatory networks of this axis and delineating its crosstalk with other signaling cascades.These investigations will provide mechanistic insights for developing targeted therapeutic strategies for associated disorders and potentially facilitate drug repurposing across diverse disease contexts.展开更多
The limited efficacy of conventional cytotoxic treatment regimes for advanced gastrointestinal neuroendocrine cancers emphasizes the need for novel and more effective medical treatment options. Recent findings on the ...The limited efficacy of conventional cytotoxic treatment regimes for advanced gastrointestinal neuroendocrine cancers emphasizes the need for novel and more effective medical treatment options. Recent findings on the specific biological features of this family of neoplasms has led to the development of new targeted therapies, which take into account the high vascularization and abundant expression of specific growth factors and cognate tyrosine kinase receptors. This review will briefly summarize the status and future perspectives of antiangiogenic, mTOR- or growth factor receptor-based pharmacological approaches for the innovative treatment of gastrointestinal neuroendocrine tumors. In view of the multitude of novel targeted approaches, the rationale for innovative combination therapies, i.e. combining growth factor (receptor)-targeting agents with chemo- or biotherapeutics or with other novel anticancer drugs such as HDAC or proteasome inhibitors will be taken into account.展开更多
SARS-CoV-2 continues to propagate globally,posing non-negligible risks of severe COVID-19.Although several clinical antivirals and immunosuppressants offer crucial protection,there is a persistent need for additional ...SARS-CoV-2 continues to propagate globally,posing non-negligible risks of severe COVID-19.Although several clinical antivirals and immunosuppressants offer crucial protection,there is a persistent need for additional therapeutic options to counter emerging viral variants and drug resistances.New strategies focusing on host targets,or simultaneously suppressing viral replication and inflammation,particularly require rigorous validation.Compared to established antiviral targets,PLpro presents an alternative actionable vulnerability in SARS-CoV-2 infection.Meanwhile,RIPK1 was pinpointed to enhance both viral replication and the resulting cytokine storm in host cells.However,inhibitors targeting PLpro or RIPK1 require further optimization for preclinical studies,and their combined efficacy in vivo has yet to be explored.Here,we report the discoveries of potent and selective PLpro inhibitors and RIPK1 inhibitors through high-throughput approaches.Our lead compounds,SHY1643 and QY1892,demonstrated synergistic and robust effects in reducing the viral loads and cytokine release syndromes in SARS-CoV-2-infected mice.These findings establish a proof-of-concept combination therapy strategy for treating severe COVID-19,and provide promising leads for the clinical drug development.展开更多
Growth factors and their corresponding receptors are commonly overexpressed and/or dysregulated in many cancers including hepatocellular cancer （HCC）. Clinical trials indicate that growth factor receptors and their ...Growth factors and their corresponding receptors are commonly overexpressed and/or dysregulated in many cancers including hepatocellular cancer （HCC）. Clinical trials indicate that growth factor receptors and their related signalling pathways play important roles in HCC cancer etiology and progression, thus providing rational targets for innovative cancer therapies. A number of strategies including monoclonal antibodies, tyrosine kinase inhibitors （＂small molecule inhibitors＂） and antisense oligonucleotides have already been evaluated for their potency to inhibit the activity and downstream signalling cascades of these receptors in HCC. First clinical trials have also shown that multi-kinase inhibition is an effective novel treatment strategy in HCC. In this respect sorafenib, an inhibitor of Raf-, VEGF- and PDGF-signalling, is the first multi-kinase inhibitor that has been approved by the FDA for the treatment of advanced HCC. Moreover, the serine-threonine kinase of mammalian target of rapamycin （mTOR） upon which the signalling of several growth factor receptors converge plays a central role in cancer cell proliferation, roTOR inhibition of HCC is currently also being studied in preclinical trials. As HCCs represent hypervascularized neoplasms, inhibition of tumour vessel formation via interfering with the VEGF/VEGFR system is another promising approach in HCC treatment. This review will summarize the current status of the various growth factor receptor-based treatment strategies and in view of the multitude of novel targeted approaches, the rationale for combination therapies for advanced HCC treatment will also be taken into account.展开更多
Protein neddylation is catalyzed by a three-enzyme cascade,namely an E1 NEDD8-activating enzyme(NAE),one of two E2 NEDD8 conjugation enzymes and one of several E3 NEDD8 ligases.The physiological substrates of neddylat...Protein neddylation is catalyzed by a three-enzyme cascade,namely an E1 NEDD8-activating enzyme(NAE),one of two E2 NEDD8 conjugation enzymes and one of several E3 NEDD8 ligases.The physiological substrates of neddylation are the family members of cullin,the scaffold component of cullin RING ligases(CRLs).Currently,a potent E1 inhibitor,MLN4924,also known as pevonedistat,is in several clinical trials for anti-cancer therapy.Here we report the discovery,through virtual screening and structural modifications,of a small molecule compound HA-1141 that directly binds to NAE in both in vitro and in vivo assays and effectively inhibits neddylation of cullins 1 e5.Surprisingly,unlike MLN4924,HA-1141 also triggers non-canonical endoplasmic reticulum(ER)stress and PKR-mediated terminal integrated stress response(ISR)to activate ATF4 at an early stage,and to inhibit protein synthesis and mTORC1 activity at a later stage,eventually leading to autophagy induction.Biologically,HA-1141 suppresses growth and survival of cultured lung cancer cells and tumor growth in in vivo xenograft lung cancer models at a well-tolerated dose.Taken together,our study has identified a small molecule compound with the dual activities of blocking neddylation and triggering ER stress,leading to growth suppression of cancer cells.展开更多
Protein phosphatases play essential roles as negative regulators of kinases and signaling cascades involved in cytoskeletal organization.Protein phosphatase 2A(PP2A)is highly conserved and is the predominant serine/th...Protein phosphatases play essential roles as negative regulators of kinases and signaling cascades involved in cytoskeletal organization.Protein phosphatase 2A(PP2A)is highly conserved and is the predominant serine/threonine phosphatase in the nervous system,constituting more than 70%of all neuronal phosphatases.PP2A is involved in diverse regulatory functions,including cell cycle progression,apoptosis,and DNA repair.Although PP2A has historically been identified as a tumor suppressor,inhibition of PP2A has paradoxically demonstrated potential as a therapeutic target for various cancers.LB100,a water-soluble,small-molecule competitive inhibitor of PP2A,has shown particular promise as a chemo-and radio-sensitizing agent.Preclinical success has led to a profusion of clinical trials on LB100 adjuvant therapies,including a phase I trial in extensive-stage small-cell lung cancer,a phase I/II trial in myelodysplastic syndrome,a phase II trial in recurrent glioblastoma,and a completed phase I trial assessing the safety of LB100 and docetaxel in various relapsed solid tumors.Herein,we review the development of LB100,the role of PP2A in cancer biology,and recent advances in targeting PP2A inhibition in immunotherapy.展开更多
The limited efficacy of cytotoxic therapy for advanced biliary tract and gallbladder cancers emphasizes the need for novel and more effective medical treatment options. A better understanding of the specific biologica...The limited efficacy of cytotoxic therapy for advanced biliary tract and gallbladder cancers emphasizes the need for novel and more effective medical treatment options. A better understanding of the specific biological features of these neoplasms led to the development of new targeted therapies, which take the abundant expression of several growth factors and cognate tyrosine kinase receptors into account. This review will briefly summarize the status and future perspectives of antiangiogenic and growth factor receptor-based pharmacological approaches for the treatment of biliary tract and gallbladder cancers. In view of multiple novel targeted approaches, the rationale for innovative therapies, such as combinations of growth factor (receptor)-targeting agents with cytotoxic drugs or with other novel anticancer drugs will be highlighted.展开更多
Mycobacterium tuberculosis(MTB) utilizes multiple mechanisms to obtain antibiotic resistance during the treatment of infections. In addition, the biofilms, secreted by MTB, can further protect the latter from the cont...Mycobacterium tuberculosis(MTB) utilizes multiple mechanisms to obtain antibiotic resistance during the treatment of infections. In addition, the biofilms, secreted by MTB, can further protect the latter from the contact with drug molecules and immune cells. These self-defending mechanisms lay a formidable challenge to develop effective therapeutic agents against chronic and recurring antibiotictolerant MTB infections. Although several inexpensive and effective drugs(isoniazid, rifampicin, pyrazinamide and ethambutol) have been discovered for the treatment regimen, MTB continues to cause considerable morbidity and mortality worldwide. Antibiotic resistance and tolerance remain major global issues, and innovative therapeutic strategies are urgently needed to address the challenges associated with pathogenic bacteria. Gratifyingly, the cell wall synthesis of tubercle bacilli requires the participation of many enzymes which exclusively exist in prokaryotic organisms. These enzymes, absent in human hepatocytes, are recognized as promising targets to develop anti-tuberculosis drug. In this paper, we discussed the critical roles of potential drug targets in regulating cell wall synthesis of MTB. And also, we systematically reviewed the advanced development of novel bioactive compounds or drug leads for inhibition of cell wall synthesis, including their discovery, chemical modification, in vitro and in vivo evaluation.展开更多
Pancreatic cancer is a dismal disease with high incidence and poor survival rates.With the aim to improve overall survival of pancreatic cancer patients,new therapeutic approaches are urgently needed.Protein kinases a...Pancreatic cancer is a dismal disease with high incidence and poor survival rates.With the aim to improve overall survival of pancreatic cancer patients,new therapeutic approaches are urgently needed.Protein kinases are key regulatory players in basically all stages of development,maintaining physiologic functions but also being involved in pathogenic processes.c-Jun N-terminal kinases(JNK)and p38 kinases,representatives of the mitogen-activated protein kinases,as well as the casein kinase 1(CK1)family of protein kinases are important mediators of adequate response to cellular stress following inflammatory and metabolic stressors,DNA damage,and others.In their physiologic roles,they are responsible for the regulation of cell cycle progression,cell proliferation and differentiation,and apoptosis.Dysregulation of the underlying pathways consequently has been identified in various cancer types,including pancreatic cancer.Pharmacological targeting of those pathways has been the field of interest for several years.While success in earlier studies was limited due to lacking specificity and off-target effects,more recent improvements in small molecule inhibitor design against stress-activated protein kinases and their use in combination therapies have shown promising in vitro results.Consequently,targeting of JNK,p38,and CK1 protein kinase family members may actually be of particular interest in the field of precision medicine in patients with highly deregulated kinase pathways related to these kinases.However,further studies are warranted,especially involving in vivo investigation and clinical trials,in order to advance inhibition of stress-activated kinases to the field of translational medicine.展开更多
BACKGROUND Breast cancer brain metastasis(BCBM)is an advanced breast disease that is difficult to treat and is associated with a high risk of death.Patient prognosis is usually poor,with reduced quality of life.In thi...BACKGROUND Breast cancer brain metastasis(BCBM)is an advanced breast disease that is difficult to treat and is associated with a high risk of death.Patient prognosis is usually poor,with reduced quality of life.In this context,we report the case of a patient with HER-2-positive BCBM treated with a macromolecular mAb(ine-tetamab)combined with a small molecule tyrosine kinase inhibitor(TKI).CASE SUMMARY The patient was a 58-year-old woman with a 12-year history of type 2 diabetes.She was compliant with regular insulin treatment and had good blood glucose control.The patient was diagnosed with invasive carcinoma of the right breast(T3N1M0 stage IIIa,HER2-positive type)through aspiration biopsy of the ipsilateral breast due to the discovery of a breast tumor in February 2019.Immunohistochemistry showed ER(-),PR(-),HER-2(3+),and Ki-67(55-60%+).Preoperative neoadjuvant chemotherapy,i.e.,the AC-TH regimen(epirubicin,cyclophosphamide,docetaxel-paclitaxel,and trastuzumab),was administered for 8 cycles.She underwent modified radical mastectomy of the right breast in November 2019 and received tocilizumab targeted therapy for 1 year.Brain metastasis was found 9 mo after surgery.She underwent brain metastasectomy in August 2020.Immunohistochemistry showed ER(-)and PR.(-),HER-2(3+),and Ki-67(10-20%+).In November 2020,the patient experienced headache symptoms.After an examination,tumor recurrence in the original surgical region of the brain was observed,and the patient was treated with inetetamab,pyrotinib,and capecitabine.Whole-brain radiotherapy was recommended.The patient and her family refused radiotherapy for personal reasons.In September 2021,a routine examination revealed that the brain tumor was considerably larger.The original systemic treatment was continued and combined with intensity-modulated radiation therapy for brain metastases,followed by regular hospitalization and routine examinations.The patient’s condition is generally stable,and she has a relatively high quality of life.This case report demonstrates that in patients with BCBM and resistance to trastuzumab,inetetamab combined with pyrotinib and chemotherapy can prolong survival.CONCLUSION Inetetamab combined with small molecule TKI drugs,chemotherapy and radiation may be an effective regimen for maintaining stable disease in patients with BCBM.展开更多
Glioblastoma(GBM)is the most common invasive malignant tumor in human brain tumors,representing the most severe grade of gliomas.Despite existing therapeutic approaches,patient prognosis remains dismal,necessitating t...Glioblastoma(GBM)is the most common invasive malignant tumor in human brain tumors,representing the most severe grade of gliomas.Despite existing therapeutic approaches,patient prognosis remains dismal,necessitating the exploration of novel strategies to enhance treatment efficacy and extend survival.Due to the restrictive nature of the blood-brain barrier(BBB),smallmolecule inhibitors are prioritized in the treatment of central nervous system tumors.Among these,DNA damage response(DDR)inhibitors have garnered significant attention due to their potent therapeutic potential across various malignancies.This review provides a detailed analysis of DDR pathways as therapeutic targets in GBM,summarizes recent advancements,therapeutic strategies,and ongoing clinical trials,and offers perspectives on future directions in this rapidly evolving field.The goal is to present a comprehensive outlook on the potential of DDR inhibitors in improving GBM management and outcomes.展开更多
EZH2 is an important target in a variety of tumors, but its role in KIRP (Kidney renal papillary cell carcinoma) has not yet been proven. The aim of this study was to investigate the role of EZH2 in KIRP patients. And...EZH2 is an important target in a variety of tumors, but its role in KIRP (Kidney renal papillary cell carcinoma) has not yet been proven. The aim of this study was to investigate the role of EZH2 in KIRP patients. And to investigate the KIRP, we used two KIRP cell lines, SKRC39 and ACHN in this study. We used CCK8 assay and colony formation assay to study the effect of EHZ2 small molecule inhibitor EPZ6438 on cancer cell proliferation, we used Trypan Blue cell counting experiments to study the effect of EZH2 on cancer cell apoptosis, and we also used qRT-PCR to study the mechanism of EZH2 on cancer cell proliferation. The results showed that EZH2 was elevated in KIRP patients;inhibition of EZH2 could inhibit the proliferation of cancer cells and induce the apoptosis of cancer cells, which is valuable for the control of KIRP in patients. As for the mechanism, we found that inhibition of EZH2 upregulated P53 expression and thus activated this tumor suppressor gene, indicating why EHZ1 inhibits renal cancer cells.展开更多
Glioblastoma(GBM)is the most common aggressive malignant tumor in brain neuroepithelial tumors and remains incurable.A variety of treatment options are currently being explored to improve patient survival,including sm...Glioblastoma(GBM)is the most common aggressive malignant tumor in brain neuroepithelial tumors and remains incurable.A variety of treatment options are currently being explored to improve patient survival,including small molecule inhibitors,viral therapies,cancer vaccines,and monoclonal antibodies.Among them,the unique advantages of small molecule inhibitors have made them a focus of attention in the drug discovery of glioblastoma.Currently,the most used chemotherapeutic agents are small molecule inhibitors that target key dysregulated signaling pathways in glioblastoma,including receptor tyrosine kinase,PI3K/AKT/mTOR pathway,DNA damage response,TP53 and cell cycle inhibitors.This review analyzes the therapeutic benefit and clinical development of novel small molecule inhibitors discovered as promising anti-glioblastoma agents by the related targets of these major pathways.Meanwhile,the recent advances in temozolomide resistance and drug combination are also reviewed.In the last part,due to the constant clinical failure of targeted therapies,this paper reviewed the research progress of other therapeutic methods for glioblastoma,to provide patients and readers with a more comprehensive understanding of the treatment landscape of glioblastoma.展开更多
Sclerostin, a protein secreted from osteocytes, negatively regulates the WNT signaling pathway by binding to the LRP5/6 co-receptors and further inhibits bone formation and promotes bone resorption. Sclerostin contrib...Sclerostin, a protein secreted from osteocytes, negatively regulates the WNT signaling pathway by binding to the LRP5/6 co-receptors and further inhibits bone formation and promotes bone resorption. Sclerostin contributes to musculoskeletal system-related diseases, making it a promising therapeutic target for the treatment of WNT-related bone diseases. Additionally, emerging evidence indicates that sclerostin contributes to the development of cancers, obesity, and diabetes, suggesting that it may be a promising therapeutic target for these diseases. Notably, cardiovascular diseases are related to the protective role of sclerostin. In this review, we summarize three distinct types of inhibitors targeting sclerostin, monoclonal antibodies, aptamers, and small-molecule inhibitors, from which monoclonal antibodies have been developed. As the first-in-class sclerostin inhibitor approved by the U.S. FDA,the monoclonal antibody romosozumab has demonstrated excellent effectiveness in the treatment of postmenopausal osteoporosis;however, it conferred high cardiovascular risk in clinical trials. Furthermore,romosozumab could only be administered by injection, which may cause compliance issues for patients who prefer oral therapy. Considering these above safety and compliance concerns, we therefore present relevant discussion and offer perspectives on the development of next-generation sclerostin inhibitors by following several ways, such as concomitant medication, artificial intelligence-based strategy, druggable modification, and bispecific inhibitors strategy.展开更多
Modulation of protein fate decision and protein homeostasis plays a significant role in altering the protein level,which acts as an orientation to develop drugs with new mechanisms.The molecular chaperones exert signi...Modulation of protein fate decision and protein homeostasis plays a significant role in altering the protein level,which acts as an orientation to develop drugs with new mechanisms.The molecular chaperones exert significant biological functions on modulation of protein fate decision and protein homeostasis under constantly changing environmental conditions through extensive protein-protein interactions(PPIs)with their client proteins.With the help of molecular chaperone machinery the processes of protein folding,trafficking,quality control and degradation of client proteins could be arranged properly.The core members of molecular chaperones,including heat shock proteins(HSPs)family and their co-chaperones,are emerging as potential drug targets since they are involved in numerous disease conditions.Development of small molecule modulators targeting not only chaperones themselves but also the PPIs among chaperones,co-chaperones and clients is attracting more and more attention.These modulators are widely used as chemical tools to study chaperone networks as well as potential drug candidates for a broader set of diseases.Here,we reviewed the key checkpoints of molecular chaperone machinery HSPs as well as their co-chaperones to discuss the small molecules targeting on them for modulation of protein fate decision.展开更多
In the past 20 years,patients with rheumatoid arthritis(RA),Crohn’s disease(CD),and other immune diseases have witnessed the impact of a great treatment advance with the availability of biological TNFa inhibitors.Wit...In the past 20 years,patients with rheumatoid arthritis(RA),Crohn’s disease(CD),and other immune diseases have witnessed the impact of a great treatment advance with the availability of biological TNFa inhibitors.With 5 approved anti-TNFa biologics on the market and soon available biosimilars,patients have more treatment options and have benefited from understanding the biology of TNFa.Nevertheless,many unmet needs remain for people living with TNFa-related diseases,namely some side effects and tolerance of current anti-TNFa biologics and resistance to therapies.Furthermore,common diseases such as osteoarthritis and back/neck pain may respond to anti-TNFa therapies at early onset of symptoms.Development of new TNFa inhibitors focusing on TNFR1 specific inhibitors,preferably small molecules that can be delivered orally,is much needed.展开更多
文摘[Objectives]To explore the synthetic process of PD-L1 small molecule inhibitors,focusing on optimizing key reaction conditions and synthetic routes.[Methods]By analyzing the pharmacophore design of PD-L1 small molecule inhibitors and combining the optimization of synthetic methods and the improvement of reaction conditions,an efficient synthetic process was developed.[Results]Through optimization of reaction conditions,not only were the purity and yield of the products improved,but the inhibitory activity of the compounds was also significantly enhanced.Some compounds demonstrated strong anti-tumor effects in both in vitro and in vivo models.[Conclusions]This study aims to provide theoretical support and technical guidance for the efficient synthesis of small molecule inhibitors,offering new ideas and practical foundations for drug development in tumor immunotherapy.
文摘This paper analyzes challenges encountered during the scale-up production of small molecule inhibitors,focusing on synthesis efficiency,solubility/bioavailability,quality control,stability/storage,and side effect prediction/control.To address these issues,targeted solutions leveraging modern technologies are proposed and implemented:synthesis efficiency and purity were significantly enhanced through process optimization,green chemistry principles,and efficient catalysts;solubility and bioavailability were improved utilizing solid dispersion and nano-crystal technologies;process scale-up was optimized with online monitoring systems and continuous flow chemistry,ensuring product quality consistency;computer-aided drug design(CADD)was employed to predict and mitigate potential side effects.These integrated approaches effectively addressed key bottlenecks in the industrial-scale manufacturing of small molecule inhibitors.
基金This work was supported by the National Natural Science Foundation of China(Nos.81904178,82073311)"Hundred Talents Program"of the Hospital of Chengdu University of Traditional Chinese Medicine(Nos.20-Q03,20-Q08).
文摘The RAS/mitogen-activated protein kinase(MAPK)pathway disorder induced by the missense mutations in the tyrosine-protein phosphatase non-receptor type 11(PTPN11)gene which resulted in the nonreceptor protein tyrosine phosphatase SHP2 dysfunction has been reported in many lung cancer cases.Moreover,the Src homology region 2(SH2)-containing protein tyrosine phosphatase 2(SHP2)mutation or deletion triggers multiple signaling pathway dysfunctions including RAS/MAPK,RAS/extracellular-signal-regulated kinase(ERK),phosphatidylinositol 3-kinase(PI3K)/protein kinase B(AKT),Janus kinase/signal transducers and activators of transcription(JAK/STAT)and Hippo/yes-associated protein(YAP)which affect the expression of growth factors,cytokines and hormones.In recent years,the developing of the small molecule SHP2 inhibitors received a lot of attention.In this review,we summarize the recent years'progresses of the SHP2 inhibitors development for the lung cancer treatment.
基金supported by grants from the National Key Research and Development Program of China(No.2023YFA1800403)The Science and Technology Commission of Shanghai Municipality(No.21S11907800)Key Research and Development Program of Ningxia(No.2023BEG02010).
文摘Signal transducer and activator of transcription 3(STAT3)is a member of the transcription factors involved in regulating many physiological and pathological processes,such as cell proliferation,angiogenesis and immune escape.STAT3 has been identified as a potential therapeutic target for various cancers.Although numerous STAT3 inhibitors have been discovered and optimized to directly inhibit STAT3 activity,they are not yet authorized for clinical use and only a few have entered clinical trials.Furthermore,several proteolysis-targeting chimera(PROTAC)molecules with STAT3 degrading effects have been developed.The event-driven action of PROTAC overcome the drawbacks of STAT3,a traditional undruggable target,and addressed possible resistance to small-molecule inhibitors by degrading the entire STAT3 protein.In this review,we presented a brief introduction to STAT3 and its functions in various cancers,and systematically overviewed the pharmacological effects of inhibitors targeting different domains of STAT3 in the last three years,the structural characterization of the main scaffold,the design strategies,and the pharmacological activities of the substituents.Also,the binding patterns and interactions of some inhibitors with STAT3 were analyzed in detail and the recent advances in STAT3 degraders are also summarized.We anticipate that this perspective will contribute to the design and optimize more novel effective and specific STAT3 inhibitors or degraders for carcinoma treatment.
基金supported by the National Natural Science Foundation of China,No.82301382the Natural Science Foundation of Hebei Province,No.H2022316001+1 种基金Government Funded Clinical Medicine Excellent Talents Project,No.ZF2023126the Postdoctoral Research Support Program for Clinical Medicine of Hebei Medical University,No.PD2023004(all to QZ).
文摘An increasing amount of evidence shows that type I interferon response,which is induced by cyclic guanosine monophosphate-adenosine monophosphate synthase(cGAS)and stimulator of interferon genes(STING)is closely associated with health and neuroinflammatory diseases.Abnormal activation or loss of control of the cGAS-STING axis affects the development of neuroinflammation.Thus,we examined its role in major neurological diseases,including traumatic brain injury,Alzheimer’s disease,Parkinson’s disease,Huntington’s disease,multiple sclerosis,herpes simplex encephalitis,and ataxia-telangiectasia.Additionally,targeted intervention of the cGAS-STING axis to control neuroinflammation and treat related diseases has become the focus of current clinical research.This article describes the development of cGAS inhibitors and small molecules that target the cGAS-STING axis and explores the potential applications of STING inhibitors and agonists in clinical research.In summary,the cGAS-STING axis may impact neurological diseases more than a single protein or gene.Future studies should focus on elucidating the functional dynamics and regulatory networks of this axis and delineating its crosstalk with other signaling cascades.These investigations will provide mechanistic insights for developing targeted therapeutic strategies for associated disorders and potentially facilitate drug repurposing across diverse disease contexts.
文摘The limited efficacy of conventional cytotoxic treatment regimes for advanced gastrointestinal neuroendocrine cancers emphasizes the need for novel and more effective medical treatment options. Recent findings on the specific biological features of this family of neoplasms has led to the development of new targeted therapies, which take into account the high vascularization and abundant expression of specific growth factors and cognate tyrosine kinase receptors. This review will briefly summarize the status and future perspectives of antiangiogenic, mTOR- or growth factor receptor-based pharmacological approaches for the innovative treatment of gastrointestinal neuroendocrine tumors. In view of the multitude of novel targeted approaches, the rationale for innovative combination therapies, i.e. combining growth factor (receptor)-targeting agents with chemo- or biotherapeutics or with other novel anticancer drugs such as HDAC or proteasome inhibitors will be taken into account.
基金supported by grants from the National Key R&D Program(2023YFC260630 to Li Tan,Gang Xu and Yuzheng Zhou,China)National Natural Science Foundation of China(82151212 to Zheng Zhang and Li Tan,and 32170755 to Ying Li)+3 种基金the Strategic Priority Research Program of the Chinese Academy of Sciences(XDB1060000 to Li Tan)Shenzhen Science and Technology Program(JCYJ20220818103017036 to Zheng Zhang,China)Shanghai Basic Research Pioneer Project(Li Tan)Shanghai Municipal Science and Technology Major Project(Li Tan).
文摘SARS-CoV-2 continues to propagate globally,posing non-negligible risks of severe COVID-19.Although several clinical antivirals and immunosuppressants offer crucial protection,there is a persistent need for additional therapeutic options to counter emerging viral variants and drug resistances.New strategies focusing on host targets,or simultaneously suppressing viral replication and inflammation,particularly require rigorous validation.Compared to established antiviral targets,PLpro presents an alternative actionable vulnerability in SARS-CoV-2 infection.Meanwhile,RIPK1 was pinpointed to enhance both viral replication and the resulting cytokine storm in host cells.However,inhibitors targeting PLpro or RIPK1 require further optimization for preclinical studies,and their combined efficacy in vivo has yet to be explored.Here,we report the discoveries of potent and selective PLpro inhibitors and RIPK1 inhibitors through high-throughput approaches.Our lead compounds,SHY1643 and QY1892,demonstrated synergistic and robust effects in reducing the viral loads and cytokine release syndromes in SARS-CoV-2-infected mice.These findings establish a proof-of-concept combination therapy strategy for treating severe COVID-19,and provide promising leads for the clinical drug development.
文摘Growth factors and their corresponding receptors are commonly overexpressed and/or dysregulated in many cancers including hepatocellular cancer （HCC）. Clinical trials indicate that growth factor receptors and their related signalling pathways play important roles in HCC cancer etiology and progression, thus providing rational targets for innovative cancer therapies. A number of strategies including monoclonal antibodies, tyrosine kinase inhibitors （＂small molecule inhibitors＂） and antisense oligonucleotides have already been evaluated for their potency to inhibit the activity and downstream signalling cascades of these receptors in HCC. First clinical trials have also shown that multi-kinase inhibition is an effective novel treatment strategy in HCC. In this respect sorafenib, an inhibitor of Raf-, VEGF- and PDGF-signalling, is the first multi-kinase inhibitor that has been approved by the FDA for the treatment of advanced HCC. Moreover, the serine-threonine kinase of mammalian target of rapamycin （mTOR） upon which the signalling of several growth factor receptors converge plays a central role in cancer cell proliferation, roTOR inhibition of HCC is currently also being studied in preclinical trials. As HCCs represent hypervascularized neoplasms, inhibition of tumour vessel formation via interfering with the VEGF/VEGFR system is another promising approach in HCC treatment. This review will summarize the current status of the various growth factor receptor-based treatment strategies and in view of the multitude of novel targeted approaches, the rationale for combination therapies for advanced HCC treatment will also be taken into account.
基金National Key R&D Program of China(2016YFA0501800 to Yi Sun)for financial support。
文摘Protein neddylation is catalyzed by a three-enzyme cascade,namely an E1 NEDD8-activating enzyme(NAE),one of two E2 NEDD8 conjugation enzymes and one of several E3 NEDD8 ligases.The physiological substrates of neddylation are the family members of cullin,the scaffold component of cullin RING ligases(CRLs).Currently,a potent E1 inhibitor,MLN4924,also known as pevonedistat,is in several clinical trials for anti-cancer therapy.Here we report the discovery,through virtual screening and structural modifications,of a small molecule compound HA-1141 that directly binds to NAE in both in vitro and in vivo assays and effectively inhibits neddylation of cullins 1 e5.Surprisingly,unlike MLN4924,HA-1141 also triggers non-canonical endoplasmic reticulum(ER)stress and PKR-mediated terminal integrated stress response(ISR)to activate ATF4 at an early stage,and to inhibit protein synthesis and mTORC1 activity at a later stage,eventually leading to autophagy induction.Biologically,HA-1141 suppresses growth and survival of cultured lung cancer cells and tumor growth in in vivo xenograft lung cancer models at a well-tolerated dose.Taken together,our study has identified a small molecule compound with the dual activities of blocking neddylation and triggering ER stress,leading to growth suppression of cancer cells.
基金the NIH Medical Research Scholars Program, a public-private partnership supported jointly by the NIH and contributions to the Foundation for the NIH from the Doris Duke Charitable Foundationthe American Association for Dental Research+2 种基金the Colgate-Palmolive Companyprivate donorssupported partly by the Intramural Research Program at the National Cancer Institute at the NIH
文摘Protein phosphatases play essential roles as negative regulators of kinases and signaling cascades involved in cytoskeletal organization.Protein phosphatase 2A(PP2A)is highly conserved and is the predominant serine/threonine phosphatase in the nervous system,constituting more than 70%of all neuronal phosphatases.PP2A is involved in diverse regulatory functions,including cell cycle progression,apoptosis,and DNA repair.Although PP2A has historically been identified as a tumor suppressor,inhibition of PP2A has paradoxically demonstrated potential as a therapeutic target for various cancers.LB100,a water-soluble,small-molecule competitive inhibitor of PP2A,has shown particular promise as a chemo-and radio-sensitizing agent.Preclinical success has led to a profusion of clinical trials on LB100 adjuvant therapies,including a phase I trial in extensive-stage small-cell lung cancer,a phase I/II trial in myelodysplastic syndrome,a phase II trial in recurrent glioblastoma,and a completed phase I trial assessing the safety of LB100 and docetaxel in various relapsed solid tumors.Herein,we review the development of LB100,the role of PP2A in cancer biology,and recent advances in targeting PP2A inhibition in immunotherapy.
文摘The limited efficacy of cytotoxic therapy for advanced biliary tract and gallbladder cancers emphasizes the need for novel and more effective medical treatment options. A better understanding of the specific biological features of these neoplasms led to the development of new targeted therapies, which take the abundant expression of several growth factors and cognate tyrosine kinase receptors into account. This review will briefly summarize the status and future perspectives of antiangiogenic and growth factor receptor-based pharmacological approaches for the treatment of biliary tract and gallbladder cancers. In view of multiple novel targeted approaches, the rationale for innovative therapies, such as combinations of growth factor (receptor)-targeting agents with cytotoxic drugs or with other novel anticancer drugs will be highlighted.
基金supported by National Natural Science Foundation of China (82073701,31900687)Natural Science Foundation of Jiangsu Province (SBK2019040713,China)+2 种基金the Project Program of State Key Laboratory of Natural Medicines,China Pharmaceutical University (SKLNMZZ202013)supported by Jiangsu Key Laboratory of Drug Design and Optimization,China Pharmaceutical University (No.2020KFKT-5)“Double First-Class” University Project (CPU2018GF04,China)。
文摘Mycobacterium tuberculosis(MTB) utilizes multiple mechanisms to obtain antibiotic resistance during the treatment of infections. In addition, the biofilms, secreted by MTB, can further protect the latter from the contact with drug molecules and immune cells. These self-defending mechanisms lay a formidable challenge to develop effective therapeutic agents against chronic and recurring antibiotictolerant MTB infections. Although several inexpensive and effective drugs(isoniazid, rifampicin, pyrazinamide and ethambutol) have been discovered for the treatment regimen, MTB continues to cause considerable morbidity and mortality worldwide. Antibiotic resistance and tolerance remain major global issues, and innovative therapeutic strategies are urgently needed to address the challenges associated with pathogenic bacteria. Gratifyingly, the cell wall synthesis of tubercle bacilli requires the participation of many enzymes which exclusively exist in prokaryotic organisms. These enzymes, absent in human hepatocytes, are recognized as promising targets to develop anti-tuberculosis drug. In this paper, we discussed the critical roles of potential drug targets in regulating cell wall synthesis of MTB. And also, we systematically reviewed the advanced development of novel bioactive compounds or drug leads for inhibition of cell wall synthesis, including their discovery, chemical modification, in vitro and in vivo evaluation.
基金German Research Foundation(DFG),No.TR1663/1-1 and No.KN356/9-1and Else Kröner-Fresenius-Stiftung,No.2017_A142.
文摘Pancreatic cancer is a dismal disease with high incidence and poor survival rates.With the aim to improve overall survival of pancreatic cancer patients,new therapeutic approaches are urgently needed.Protein kinases are key regulatory players in basically all stages of development,maintaining physiologic functions but also being involved in pathogenic processes.c-Jun N-terminal kinases(JNK)and p38 kinases,representatives of the mitogen-activated protein kinases,as well as the casein kinase 1(CK1)family of protein kinases are important mediators of adequate response to cellular stress following inflammatory and metabolic stressors,DNA damage,and others.In their physiologic roles,they are responsible for the regulation of cell cycle progression,cell proliferation and differentiation,and apoptosis.Dysregulation of the underlying pathways consequently has been identified in various cancer types,including pancreatic cancer.Pharmacological targeting of those pathways has been the field of interest for several years.While success in earlier studies was limited due to lacking specificity and off-target effects,more recent improvements in small molecule inhibitor design against stress-activated protein kinases and their use in combination therapies have shown promising in vitro results.Consequently,targeting of JNK,p38,and CK1 protein kinase family members may actually be of particular interest in the field of precision medicine in patients with highly deregulated kinase pathways related to these kinases.However,further studies are warranted,especially involving in vivo investigation and clinical trials,in order to advance inhibition of stress-activated kinases to the field of translational medicine.
文摘BACKGROUND Breast cancer brain metastasis(BCBM)is an advanced breast disease that is difficult to treat and is associated with a high risk of death.Patient prognosis is usually poor,with reduced quality of life.In this context,we report the case of a patient with HER-2-positive BCBM treated with a macromolecular mAb(ine-tetamab)combined with a small molecule tyrosine kinase inhibitor(TKI).CASE SUMMARY The patient was a 58-year-old woman with a 12-year history of type 2 diabetes.She was compliant with regular insulin treatment and had good blood glucose control.The patient was diagnosed with invasive carcinoma of the right breast(T3N1M0 stage IIIa,HER2-positive type)through aspiration biopsy of the ipsilateral breast due to the discovery of a breast tumor in February 2019.Immunohistochemistry showed ER(-),PR(-),HER-2(3+),and Ki-67(55-60%+).Preoperative neoadjuvant chemotherapy,i.e.,the AC-TH regimen(epirubicin,cyclophosphamide,docetaxel-paclitaxel,and trastuzumab),was administered for 8 cycles.She underwent modified radical mastectomy of the right breast in November 2019 and received tocilizumab targeted therapy for 1 year.Brain metastasis was found 9 mo after surgery.She underwent brain metastasectomy in August 2020.Immunohistochemistry showed ER(-)and PR.(-),HER-2(3+),and Ki-67(10-20%+).In November 2020,the patient experienced headache symptoms.After an examination,tumor recurrence in the original surgical region of the brain was observed,and the patient was treated with inetetamab,pyrotinib,and capecitabine.Whole-brain radiotherapy was recommended.The patient and her family refused radiotherapy for personal reasons.In September 2021,a routine examination revealed that the brain tumor was considerably larger.The original systemic treatment was continued and combined with intensity-modulated radiation therapy for brain metastases,followed by regular hospitalization and routine examinations.The patient’s condition is generally stable,and she has a relatively high quality of life.This case report demonstrates that in patients with BCBM and resistance to trastuzumab,inetetamab combined with pyrotinib and chemotherapy can prolong survival.CONCLUSION Inetetamab combined with small molecule TKI drugs,chemotherapy and radiation may be an effective regimen for maintaining stable disease in patients with BCBM.
基金supported by the National Natural Science Foundation of China(No.82173652)the Natural Science Foundation of Jiangsu Province(Nos.BK20191411 and BK20221522)+1 种基金Jiangsu“333 High Level Talents Cultivation”Leading Talents(2022-3-16-203)the Qing Lan Project to SUN Haopeng。
文摘Glioblastoma(GBM)is the most common invasive malignant tumor in human brain tumors,representing the most severe grade of gliomas.Despite existing therapeutic approaches,patient prognosis remains dismal,necessitating the exploration of novel strategies to enhance treatment efficacy and extend survival.Due to the restrictive nature of the blood-brain barrier(BBB),smallmolecule inhibitors are prioritized in the treatment of central nervous system tumors.Among these,DNA damage response(DDR)inhibitors have garnered significant attention due to their potent therapeutic potential across various malignancies.This review provides a detailed analysis of DDR pathways as therapeutic targets in GBM,summarizes recent advancements,therapeutic strategies,and ongoing clinical trials,and offers perspectives on future directions in this rapidly evolving field.The goal is to present a comprehensive outlook on the potential of DDR inhibitors in improving GBM management and outcomes.
文摘EZH2 is an important target in a variety of tumors, but its role in KIRP (Kidney renal papillary cell carcinoma) has not yet been proven. The aim of this study was to investigate the role of EZH2 in KIRP patients. And to investigate the KIRP, we used two KIRP cell lines, SKRC39 and ACHN in this study. We used CCK8 assay and colony formation assay to study the effect of EHZ2 small molecule inhibitor EPZ6438 on cancer cell proliferation, we used Trypan Blue cell counting experiments to study the effect of EZH2 on cancer cell apoptosis, and we also used qRT-PCR to study the mechanism of EZH2 on cancer cell proliferation. The results showed that EZH2 was elevated in KIRP patients;inhibition of EZH2 could inhibit the proliferation of cancer cells and induce the apoptosis of cancer cells, which is valuable for the control of KIRP in patients. As for the mechanism, we found that inhibition of EZH2 upregulated P53 expression and thus activated this tumor suppressor gene, indicating why EHZ1 inhibits renal cancer cells.
基金We gratefully thank the support from the grants(Nos.82173652,81872728,81830105 and 81973207)of National Natural Science Foundation of China(Nos.BK20191411)of Natural Science Foundation of Jiangsu Province.
文摘Glioblastoma(GBM)is the most common aggressive malignant tumor in brain neuroepithelial tumors and remains incurable.A variety of treatment options are currently being explored to improve patient survival,including small molecule inhibitors,viral therapies,cancer vaccines,and monoclonal antibodies.Among them,the unique advantages of small molecule inhibitors have made them a focus of attention in the drug discovery of glioblastoma.Currently,the most used chemotherapeutic agents are small molecule inhibitors that target key dysregulated signaling pathways in glioblastoma,including receptor tyrosine kinase,PI3K/AKT/mTOR pathway,DNA damage response,TP53 and cell cycle inhibitors.This review analyzes the therapeutic benefit and clinical development of novel small molecule inhibitors discovered as promising anti-glioblastoma agents by the related targets of these major pathways.Meanwhile,the recent advances in temozolomide resistance and drug combination are also reviewed.In the last part,due to the constant clinical failure of targeted therapies,this paper reviewed the research progress of other therapeutic methods for glioblastoma,to provide patients and readers with a more comprehensive understanding of the treatment landscape of glioblastoma.
基金supported by the National Key R&D Program of China (2018YFA0800802)Hong Kong General Research Fund (HKBU 12114416,HKBU 12101117,HKBU 12100918,HKBU 12101018,HKBU 12103519,HKBU 14100218,CUHK 14108816,CUHK 14100218,CUHK 14103420,China)+3 种基金Direct Grant of The Chinese University of Hong Kong (2018.094,China)Interdisciplinary Research Clusters Matching Scheme of Hong Kong Baptist University (RC-IRCs/17-18/02,China)Guangdong Basic and Applied Basic Research Foundation (2019B1515120089,China)Science and Technology Innovation Commission of Shenzhen Municipality Funds (JCYJ20160229210357960,China)。
文摘Sclerostin, a protein secreted from osteocytes, negatively regulates the WNT signaling pathway by binding to the LRP5/6 co-receptors and further inhibits bone formation and promotes bone resorption. Sclerostin contributes to musculoskeletal system-related diseases, making it a promising therapeutic target for the treatment of WNT-related bone diseases. Additionally, emerging evidence indicates that sclerostin contributes to the development of cancers, obesity, and diabetes, suggesting that it may be a promising therapeutic target for these diseases. Notably, cardiovascular diseases are related to the protective role of sclerostin. In this review, we summarize three distinct types of inhibitors targeting sclerostin, monoclonal antibodies, aptamers, and small-molecule inhibitors, from which monoclonal antibodies have been developed. As the first-in-class sclerostin inhibitor approved by the U.S. FDA,the monoclonal antibody romosozumab has demonstrated excellent effectiveness in the treatment of postmenopausal osteoporosis;however, it conferred high cardiovascular risk in clinical trials. Furthermore,romosozumab could only be administered by injection, which may cause compliance issues for patients who prefer oral therapy. Considering these above safety and compliance concerns, we therefore present relevant discussion and offer perspectives on the development of next-generation sclerostin inhibitors by following several ways, such as concomitant medication, artificial intelligence-based strategy, druggable modification, and bispecific inhibitors strategy.
基金the financial support by National Natural Science Foundation of China(81773639,81773581,81872737 and 81930100)the Natural Science Foundation of Jiangsu Province(BK20190559,BK20160746 China)+6 种基金National Science&Technology Major Project‘Key New Drug Creation and Manufacturing Program’(Nos.2018ZX09711002 and 2017ZX09302003,China)the Priority Academic Program Development of Jiangsu Higher Education Institutionsthe Fundamental Research Funds for the Central Universities of China Pharmaceutical University(2632018ZD15,China)the Double First Class Innovation Team of China Pharmaceutical University(CPU2018GY02,China)Program for Outstanding Scientific and Technological Innovation Team of Jiangsu Higher Educationthe Young Elite Scientists Sponsorship Program by CASTthe Jiangsu Qing Lan Project
文摘Modulation of protein fate decision and protein homeostasis plays a significant role in altering the protein level,which acts as an orientation to develop drugs with new mechanisms.The molecular chaperones exert significant biological functions on modulation of protein fate decision and protein homeostasis under constantly changing environmental conditions through extensive protein-protein interactions(PPIs)with their client proteins.With the help of molecular chaperone machinery the processes of protein folding,trafficking,quality control and degradation of client proteins could be arranged properly.The core members of molecular chaperones,including heat shock proteins(HSPs)family and their co-chaperones,are emerging as potential drug targets since they are involved in numerous disease conditions.Development of small molecule modulators targeting not only chaperones themselves but also the PPIs among chaperones,co-chaperones and clients is attracting more and more attention.These modulators are widely used as chemical tools to study chaperone networks as well as potential drug candidates for a broader set of diseases.Here,we reviewed the key checkpoints of molecular chaperone machinery HSPs as well as their co-chaperones to discuss the small molecules targeting on them for modulation of protein fate decision.
基金the Department of Veterans Affairs Healthcare Network,a Penn Center for Musculoskeletal Disorders(PCMD)pilot grant(P30-AR050950-10 Pilot)a grant from the National Institute of Arthritis and Musculoskeletal and Skin Diseases(NIAMS,R21 AR071623).
文摘In the past 20 years,patients with rheumatoid arthritis(RA),Crohn’s disease(CD),and other immune diseases have witnessed the impact of a great treatment advance with the availability of biological TNFa inhibitors.With 5 approved anti-TNFa biologics on the market and soon available biosimilars,patients have more treatment options and have benefited from understanding the biology of TNFa.Nevertheless,many unmet needs remain for people living with TNFa-related diseases,namely some side effects and tolerance of current anti-TNFa biologics and resistance to therapies.Furthermore,common diseases such as osteoarthritis and back/neck pain may respond to anti-TNFa therapies at early onset of symptoms.Development of new TNFa inhibitors focusing on TNFR1 specific inhibitors,preferably small molecules that can be delivered orally,is much needed.
