Motor neuron diseases are sporadic or inherited fatal neurodegenerative conditions.They selectively affect the upper and/or lower motor neurons in the brain and spinal cord and feature a slow onset and a subacute cour...Motor neuron diseases are sporadic or inherited fatal neurodegenerative conditions.They selectively affect the upper and/or lower motor neurons in the brain and spinal cord and feature a slow onset and a subacute course contingent upon the site of damage.The main types include amyotrophic lateral sclerosis,progressive muscular atrophy,primary lateral sclerosis,and progressive bulbar palsy,the pathological processes of which are largely identical,with the main disparity lying in the location of the lesions.Amyotrophic lateral sclerosis is the representative condition in this group of diseases,while other types are its variants.Hence,this article mainly focuses on the advancements and challenges in drug research for amyotrophic lateral sclerosis but also briefly addresses several other important degenerative motor neuron diseases.Although the precise pathogenesis remains elusive,recent advancements have shed light on various theories,including gene mutation,excitatory amino acid toxicity,autoimmunology,and neurotrophic factors.The US Food and Drug Administration has approved four drugs for use in delaying the progression of amyotrophic lateral sclerosis:riluzole,edaravone,AMX0035,and tofersen,with the latter being the most recent to receive approval.However,following several phaseⅢtrials that failed to yield favorable outcomes,AMX0035 has been voluntarily withdrawn from both the US and Canadian markets.This article presents a comprehensive summary of drug trials primarily completed between January 1,2023,and June 30,2024,based on data sourced from clinicaltrials.gov.Among these trials,five are currently in phaseⅠ,seventeen are in phaseⅡ,and eleven are undergoing phaseⅢevaluation.Notably,24 clinical trials are now investigating potential disease-modifying therapy drugs,accounting for the majority of the drugs included in this review.Some promising drugs being investigated in preclinical studies,such as ATH-1105,are included in our analysis,and another review in frontiers in gene therapy and immunotherapy has demonstrated their therapeutic potential for motor neuron diseases.This article was written to be an overview of research trends and treatment prospects related to motor neuron disease drugs,with the aim of highlighting the latest potentialities for clinical therapy.展开更多
Cardiotoxicity is a critical issue in drug development that poses serious health risks,including potentially fatal arrhythmias.The human ether-à-go-go related gene(hERG)potassium channel,as one of the primary tar...Cardiotoxicity is a critical issue in drug development that poses serious health risks,including potentially fatal arrhythmias.The human ether-à-go-go related gene(hERG)potassium channel,as one of the primary targets of cardiotoxicity,has garnered widespread attention.Traditional cardiotoxicity testing methods are expensive and time-consuming,making computational virtual screening a suitable alternative.In this study,we employed machine learning techniques utilizing molecular fingerprints and descriptors to predict the cardiotoxicity of compounds,with the aim of improving prediction accuracy and efficiency.We used four types of molecular fingerprints and descriptors combined with machine learning and deep learning algorithms,including Gaussian naive Bayes(NB),random forest(RF),support vector machine(SVM),K-nearest neighbors(KNN),eXtreme gradient boosting(XGBoost),and Transformer models,to build predictive models.Our models demonstrated advanced predictive performance.The best machine learning model,XGBoost Morgan,achieved an accuracy(ACC)value of 0.84,and the deep learning model,Transformer_Morgan,achieved the best ACC value of 0.85,showing a high ability to distinguish between toxic and non-toxic compounds.On an external independent validation set,it achieved the best area under the curve(AUC)value of 0.93,surpassing ADMETlab3.0,Cardpred,and CardioDPi.In addition,we explored the integration of molecular descriptors and fingerprints to enhance model performance and found that ensemble methods,such as voting and stacking,provided slight improvements in model stability.Furthermore,the SHapley Additive exPlanations(SHAP)explanations revealed the relationship between benzene rings,fluorine-containing groups,NH groups,oxygen in ether groups,and cardiotoxicity,highlighting the importance of these features.This study not only improved the predictive accuracy of cardiotoxicity models but also promoted a more reliable and scientifically interpretable method for drug safety assessment.Using computational methods,this study facilitates a more efficient drug development process,reduces costs,and improves the safety of new drug candidates,ultimately benefiting medical and public health.展开更多
“A child receiving a single shot containing mRNA vaccines that protect against multiple diseases,all delivered with one lipid nanoparticle”—this is how Professor Drew Weissman,the 2023 Nobel laureate in Physiology ...“A child receiving a single shot containing mRNA vaccines that protect against multiple diseases,all delivered with one lipid nanoparticle”—this is how Professor Drew Weissman,the 2023 Nobel laureate in Physiology or Medicine[1],described the potential of messenger RNA(mRNA)therapy in an interview with Forbes[2].In 2024,the Nobel Prize was again awarded to RNA researchers,this time to Victor Ambros and Gary Ruvkun for the discovery of microRNA and its role in post-transcriptional gene regulation[3],further underscoring the transformative capacity of RNA therapeutics in the 21st century healthcare.展开更多
Cancer therapy continues to face major challenges,including drug resistance,toxicity,and tumor heterogeneity,which highlight the need for multitarget strategies.This review examines the molecular compatibility theory ...Cancer therapy continues to face major challenges,including drug resistance,toxicity,and tumor heterogeneity,which highlight the need for multitarget strategies.This review examines the molecular compatibility theory in integrative oncology,which combines traditional Chinese medicine(TCM)with systems biology to address these limitations.TCM formulas,such as Banxia Xiexin decoction and Qiqin Huchang formula,contain bioactive compounds(e.g.,quercetin and berberine)that modulate interconnected pathways(phosphoinositide 3-kinase/protein kinase B and mitogen-activated protein kinase)and the tumor microenvironment,thereby promoting apoptosis,inhibiting angiogenesis,and regulating immune responses.The theory modernizes TCM’s“Jun-Chen-Zuo-Shi”principle by optimizing herb combinations through network pharmacology and omics technologies.For instance,Astragalus membranaceus(Fisch.)Bge.var.mongholicus(Bge.)Hsiao(Huang Qi)-Curcuma phaeocaulis Val.(E Zhu)pairs co-target hypoxia-inducible factor 1-alpha to suppress metastasis,while artificial intelligence-driven models predict synergistic interactions such as quercetin-cyclin-dependent kinase 1 inhibition.Clinical studies have shown improved outcomes;for instance,modified Banxia Xiexin decoction reduces chemotherapy-induced toxicity in gastric cancer,and Xihuang pill enhances immunotherapy via signal transducer and activator of transcription 3-programmed death-ligand 1 modulation.Despite these advances,challenges remain in standardization and mechanistic validation.Future research should prioritize single-cell sequencing,organoid models,and international collaboration to refine personalized therapies and translate TCM into evidence-based oncology.By integrating empirical knowledge with modern science,molecular compatibility theory provides a robust framework for multitarget drug development and the advancement of integrative cancer therapies.展开更多
Artificial intelligence(AI)is revolutionizing the traditional paradigm of drug development at an unprecedented pace.With the rapid advancement of technologies such as deep learning and machine learning,AI has demonstr...Artificial intelligence(AI)is revolutionizing the traditional paradigm of drug development at an unprecedented pace.With the rapid advancement of technologies such as deep learning and machine learning,AI has demonstrated substantial potential in various aspects of pharmaceutical research,including drug target identification,molecular design,and clinical trial optimization(Figure 1).Industry reports suggest that AI has the potential to reduce the drug development timeline from the conventional 10–15 years to 2–3 years,while also slashing development costs by billions of dollars.This article provides a comprehensive analysis of the current applications and future trends of AI in drug development and discovery,focusing on three dimensions:current hotspots,challenges,and future directions.展开更多
Model-informed drug develop⁃ment(MIDD)is the application of a various math⁃ematical,statistical,and biological models to facilitate drug development,decision making and regulatory review.As a quantitative tool,MIDD ap...Model-informed drug develop⁃ment(MIDD)is the application of a various math⁃ematical,statistical,and biological models to facilitate drug development,decision making and regulatory review.As a quantitative tool,MIDD approaches allow an integration of information obtained from non-clinical studies and clinical trials in a drug development program.General understandings of the underlying biology,patho⁃physiology,and pharmacology can also be incor⁃porated into the model.MIDD is centered on knowledge and inferences generated from inte⁃grated models of the physicochemical character⁃istics of a molecule,its disposition in the body,and its mechanism of action,and how the drug might affect a disease from both an efficacy and a safety perspective.MIDD approaches have the potential to significantly streamline drug develop⁃ment,by improving clinical trial efficiency,opti⁃mizing dose and regimen and waive unneces⁃sary clinical studies.This presentation will use cases studies to demonstrate how to apply MIDD in early phase of clinical trials.展开更多
The therapeutic landscape of metastatic colorectal cancer(mCRC)has changed substantially with the emergence of new molecularly targeted agents(MTA)usedas single agents or alongside standard chemotherapy.The use of the...The therapeutic landscape of metastatic colorectal cancer(mCRC)has changed substantially with the emergence of new molecularly targeted agents(MTA)usedas single agents or alongside standard chemotherapy.The use of these MTAs extended the overall survival ofpatients with mCRC to a level that current chemotherapeutics alone could not achieve.In addition,improvement in surgical techniques and ablation modalities offer cure to a limited subset of patients with mCRC andMTAs have been found to have a significant role heretoo,as they aid resectability.However,for the majority of patients,mCRC remains an invariably incurabledisease necessitating continued courses of combinedtreatment modalities.During the course of these treatments,either cytotoxic or biological,cancer cells maintain their ability to acquire mitogenic mutations whichrender them resistant to treatment.Key challengesremain to identify appropriate subsets of patients whowill most likely benefit from these new MTAs and effectively select these based on validated biomarkers.Moreover,better knowledge of the biology of colorectal cancer and the mechanisms via which it bypasses blockade of known signalling pathways will help us design better and more rational sequencing of these treatments,so that we can maximise the survivorship of mCRC patients.This review outlines treatment strategies for known molecular alterations with new MTAs and highlights some promising strategies.展开更多
Alzheimer＇s disease （AD） is the most frequent cause of dementia in the western world. In clinical terms, AD is characterized by progres- sive cognitive decline that usually begins with memory impairment. As the dis...Alzheimer＇s disease （AD） is the most frequent cause of dementia in the western world. In clinical terms, AD is characterized by progres- sive cognitive decline that usually begins with memory impairment. As the disease progresses, AD inevitably affects all intellectual functions including executive functions, leading to complete dependence for basic activities of daily life and premature death.展开更多
Drug development in oncology is undergoing a substantial shift nowadays. The drivers for this are multi-factorial. On the one side, drug development is performed more rationally than ever, profiting from the scientifi...Drug development in oncology is undergoing a substantial shift nowadays. The drivers for this are multi-factorial. On the one side, drug development is performed more rationally than ever, profiting from the scientific advances in molecular biology in general and the elucidation of the various ＂omes＂ from genome to metabolome in particular.展开更多
Since President Obama announced the Precision Medicine Initiative from a national strategy perspective in his State of the Union address,precision medicine has rapidly become a world-wide hotspot and drawn global atte...Since President Obama announced the Precision Medicine Initiative from a national strategy perspective in his State of the Union address,precision medicine has rapidly become a world-wide hotspot and drawn global attention in the medical field.Precision medicine aims at applying genetic information of individual diseases to guide his or her diagnosis and treatment.展开更多
Modern drugs have changed epilepsy,which affects people of all ages.However,for young people with epilepsy,the framework of drug development has stalled.In the wake of the thalidomide catastrophe,the misconception eme...Modern drugs have changed epilepsy,which affects people of all ages.However,for young people with epilepsy,the framework of drug development has stalled.In the wake of the thalidomide catastrophe,the misconception emerged that for people<18 years of age drugs,including antiseizure medications(ASMs),need separate proof of efficacy and safety,overall called"pediatric drug development".For ASMs,this has changed to some degree.Authorities now accept that ASMs are effective in<18 years as well,but they still require"extrapolation of efficacy,"as if minors were another species.As a result,some of the pediatric clinical epilepsy research over the past decades was unnecessary.Even more importantly,this has hampered research on meaningful research goals.We do not need to confirm that ASMs work before as they do after the 18th birthday.Instead,we need to learn how to prevent brain damage in young patients by preventing seizures and optimize ASMs’uses.Herein we discuss how to proceed in this endeavor.展开更多
With the rapid development of modern science and technology, traditional randomized controlled trials have become insufficient to meet current scientific research needs, particularly in the field of clinical research....With the rapid development of modern science and technology, traditional randomized controlled trials have become insufficient to meet current scientific research needs, particularly in the field of clinical research. The emergence of real-world data studies, which align more closely with actual clinical evidence, has garnered significant attention in recent years. The following is a brief overview of the specific utilization of real-world data in drug development, which often involves large sample sizes and analyses covering a relatively diverse population without strict inclusion and exclusion criteria. Real-world data often reflects real clinical practice: treatment options are chosen according to the actual conditions and willingness of patients rather than through random assignment. Analysis based on real-world data also focuses on endpoints highly relevant to clinical benefits and the quality of life of patients. The booming big data technology supports the utilization of real-world data to accelerate new drug development, serving as an important supplement to traditional clinical trials.展开更多
Objective To identify the critical risks in the process of innovative drug research and development,and to provide reference for improving the efficiency of innovative drug development and risk control in China.Method...Objective To identify the critical risks in the process of innovative drug research and development,and to provide reference for improving the efficiency of innovative drug development and risk control in China.Methods Expert investigation and analytic hierarchy process were used to determine the weights of different risks.Results and Conclusion The research and analysis results showed that the risks at different stages of development had different effects on the success rate of drug development,among which the risk at the drug discovery stage influenced the most.In the drug discovery stage,inappropriate target selection had the greatest impact on the success rate of drug development.The lack of appropriate cell tissue or animal models had the greatest impact on the success rate of drug development from the discovery of a compound to the application for clinical trials.The difference in changes between nonclinical and clinical studies had the greatest impact on the success rate of drug development from early clinical studies to pivotal clinical studies.Incorrect dose selection had the greatest impact on the success rate of drug development from pivotal clinical studies to marketing authorization applications.The biggest impact from the marketing authorization application to the approval stage was inadequate communication with regulators.After investigating the weight of risk factors in the process of innovative drug development based on scientific methods,a new perspective for the risk control of new drug development and improving the research and development efficiency is provided.展开更多
advancements in first-in-class therapies and breakthrough technologies.The United States has maintained its leadership in first-in-class therapies and breakthrough technologies,driven by advanced regulatory pathways,s...advancements in first-in-class therapies and breakthrough technologies.The United States has maintained its leadership in first-in-class therapies and breakthrough technologies,driven by advanced regulatory pathways,significant multinational corporation investments,a robust Research and Development(R&D)workforce,and continuous technological innovation.Additionally,global impact of the Food and Drug Administration(FDA)is further amplified through collaborations like Project Orbis,which facilitates simultaneous reviews of cancer treatments by multiple regulatory authorities worldwide.Europe,while historically strong,faces growing challenges in maintaining its competitive edge,particularly due to protracted regulatory timelines and complex coordination among its member states.In this competitive global environment,China has rapidly transformed from a generics-dominated market to a key player in innovative drug development.This article reviews China’s progress in innovative drug R&D from 2019 to 2023,emphasizing regulatory modernization,clinical trial advancements,and the emergence of novel therapies.By comparing China’s developments with above global counterparts,this review highlights the country’s achievements in regulatory efficiency,clinical trial progress,and the development of innovative therapies such as biologics and cell and gene therapies.展开更多
The unique characteristics of the deep space environment,microgravity,cosmic radiation,and extreme temperature fluctuations,are emerging as major driving forces for pharmaceutical innovation.These factors provide new ...The unique characteristics of the deep space environment,microgravity,cosmic radiation,and extreme temperature fluctuations,are emerging as major driving forces for pharmaceutical innovation.These factors provide new avenues for optimizing drug formulations,improving crystal structure quality,and accelerating the discovery of therapeutic targets.Advances in deep space research not only help overcome critical bottlenecks in terrestrial drug development but also promote progress in structure-based drug design and deepen understanding of cellular stress-response mechanisms.Current progress in space-based pharmaceutical research primarily includes the study of disease mechanisms under microgravity,protein crystallization in microgravity,and drug development utilizing deep space radiation and resources.However,the operational complexity,high costs,and limited data reproducibility of space experiments remain key challenges hindering widespread application.Looking ahead,with the integration of automation,artificial intelligence analysis,and on-orbit manufacturing,deep space drug development is expected to achieve greater scalability and precision,opening a new frontier in biopharmaceutical science.展开更多
Viruses constitute a significant group of pathogens that have caused numerous fatalities and substantial economic losses in recent years,particularly with the emergence of coronaviruses.While the impact of SARS-CoV-2 ...Viruses constitute a significant group of pathogens that have caused numerous fatalities and substantial economic losses in recent years,particularly with the emergence of coronaviruses.While the impact of SARS-CoV-2 appears to be diminishing in daily life,only a limited number of drugs have received approval or emergency use authorization for its treatment.Given the high mutation rate of viral genomes,host-directed agents(HDAs)have emerged as a preferred choice due to their broad applicability and lasting effectiveness.In contrast to direct-acting antivirals(DAAs),HDAs offer several advantages,including broad-spectrum antiviral activities,potential efficacy against future emerging viruses,and a lower likelihood of inducing drug resistance.In our review article,we have synthesized known host-directed antiviral targets that span diverse cellular pathways and mechanisms,shedding light on the intricate interplay between host cells and viruses.Additionally,we have provided a brief overview of the development of HDAs based on these targets.We aim for this comprehensive analysis to offer valuable perspectives and insights that can guide future antiviral research and drug development efforts.展开更多
Rare diseases continue to pose a formidable public health challenge with lack or absence of effective treatments,demonstrating an immense need for rare disease drugs.However,the development of rare disease drugs remai...Rare diseases continue to pose a formidable public health challenge with lack or absence of effective treatments,demonstrating an immense need for rare disease drugs.However,the development of rare disease drugs remains uneven globally due to disparities in resource allocation,policy support,and medical infrastructure[1].Compared with other regions such as the USA and the EU,China exhibits distinct needs related to its particular disease spectrum,incidence,prevalence,genetic backgrounds,aetiology,and clinical practices[2].展开更多
Sigma-1 receptor(σ1R)has become a focus point of drug discovery for central nervous system(CNS)diseases.A series of novel 1-phenylethan-1-one O-(2-aminoethyl)oxime derivatives were synthesized.In vitro biological eva...Sigma-1 receptor(σ1R)has become a focus point of drug discovery for central nervous system(CNS)diseases.A series of novel 1-phenylethan-1-one O-(2-aminoethyl)oxime derivatives were synthesized.In vitro biological evaluation led to the identification of 1a,14a,15d and 16d as the most high-affinity(K_(i)<4 nmol/L)and selectiveσ1R agonists.Among these,15d,the most metabolically stable derivative exhibited high selectivity forσ1R in relation toσ_(2)R and 52 other human targets.In addition to low CYP450 inhibition and induction,15d also exhibited high brain permeability and excellent oral bioavailability.Importantly,15d demonstrated effective antipsychotic potency,particularly for alleviating negative symptoms and improving cognitive impairment in experimental animal models,both of which are major challenges for schizophrenia treatment.Moreover,15d produced no significant extrapyramidal symptoms,exhibiting superior pharmacological profiles in relation to current antipsychotic drugs.Mechanistically,15d inhibited GSK3βand enhanced prefrontal BDNF expression and excitatory synaptic transmission in pyramidal neurons.Collectively,these in vivo proof-of-concept findings provide substantial experimental evidence to demonstrate that modulatingσ1R represents a potential new therapeutic approach for schizophrenia.The novel chemical entity along with its favorable drug-like and pharmacological profile of 15d renders it a promising candidate for treating schizophrenia.展开更多
In vitro 3D cancer spheroids (tumoroids) exhibit a drug resistance profile similar to that found in solid tumors. 3D spheroid culture methods recreate more physiologically relevant microenvironments for cells. Therefo...In vitro 3D cancer spheroids (tumoroids) exhibit a drug resistance profile similar to that found in solid tumors. 3D spheroid culture methods recreate more physiologically relevant microenvironments for cells. Therefore, these models are more appropriate for cancer drug screening. We have recently developed a protocol for MCF-7 cell spheroid culture, and used this method to test the effects of different types of drugs on this estrogen-dependent breast cancer cell spheroid. Our results demonstrated that MCF-7 cells can grow spheroid in medium using a low attachment plate. We managed to grow one spheroid in each well, and the spheroid can grow over a month, the size of the spheroid can grow over a hundred times in volume. Our targeted drug experimental results suggest that estrogen sulfotransferase, steroid sulfatase, and G protein-coupled estrogen receptor may play critical roles in MCF-7 cell spheroid growth, while estrogen receptors α and β may not play an essential role in MCF-7 spheroid growth. Organoids are the miniatures of in vivo tissues and reiterate the in vivo microenvironment of a specific organ, best fit for the in vitro studies of diseases and drug development. Tumoroid, developed from cancer cell lines or patients’ tumor tissue, is the best in vitro model of in vivo tumors. 3D spheroid technology will be the best future method for drug development of cancers and other diseases. Our reported method can be developed clinically to develop personalized drugs when the patient’s tumor tissues are used to develop a spheroid culture for drug screening.展开更多
Over the past 30 years, China has significantly improved the drug development environment by establishing a series of policies for the regulation of new drug approval. The regulatory system for new drug evaluation and...Over the past 30 years, China has significantly improved the drug development environment by establishing a series of policies for the regulation of new drug approval. The regulatory system for new drug evaluation and registration in China was gradually developed in accordance with international standards. The approval and registration of TCM in China became as strict as those of chemical drugs and biological products. In this review, TCM-based new drug discovery and development are introduced according to the TCM classification of nine categories.展开更多
基金supported by the National Key Research and Development Program of China,No.2022YFC2703101(to YC)the National Natural Science Fundation of China,No.82371422(to YC)+1 种基金the National Innovation and Entrepreneurship Training Program for College Students,No.202310611408(to XW)the 1·3·5 Project for Disciplines of Excellence Clinical Research Fund,West China Hospital,Sichuan University,No.2023HXFH032(to YC)。
文摘Motor neuron diseases are sporadic or inherited fatal neurodegenerative conditions.They selectively affect the upper and/or lower motor neurons in the brain and spinal cord and feature a slow onset and a subacute course contingent upon the site of damage.The main types include amyotrophic lateral sclerosis,progressive muscular atrophy,primary lateral sclerosis,and progressive bulbar palsy,the pathological processes of which are largely identical,with the main disparity lying in the location of the lesions.Amyotrophic lateral sclerosis is the representative condition in this group of diseases,while other types are its variants.Hence,this article mainly focuses on the advancements and challenges in drug research for amyotrophic lateral sclerosis but also briefly addresses several other important degenerative motor neuron diseases.Although the precise pathogenesis remains elusive,recent advancements have shed light on various theories,including gene mutation,excitatory amino acid toxicity,autoimmunology,and neurotrophic factors.The US Food and Drug Administration has approved four drugs for use in delaying the progression of amyotrophic lateral sclerosis:riluzole,edaravone,AMX0035,and tofersen,with the latter being the most recent to receive approval.However,following several phaseⅢtrials that failed to yield favorable outcomes,AMX0035 has been voluntarily withdrawn from both the US and Canadian markets.This article presents a comprehensive summary of drug trials primarily completed between January 1,2023,and June 30,2024,based on data sourced from clinicaltrials.gov.Among these trials,five are currently in phaseⅠ,seventeen are in phaseⅡ,and eleven are undergoing phaseⅢevaluation.Notably,24 clinical trials are now investigating potential disease-modifying therapy drugs,accounting for the majority of the drugs included in this review.Some promising drugs being investigated in preclinical studies,such as ATH-1105,are included in our analysis,and another review in frontiers in gene therapy and immunotherapy has demonstrated their therapeutic potential for motor neuron diseases.This article was written to be an overview of research trends and treatment prospects related to motor neuron disease drugs,with the aim of highlighting the latest potentialities for clinical therapy.
基金supported by National Key Research and Development Project,China(Grant No.:2021YFA1500403).
文摘Cardiotoxicity is a critical issue in drug development that poses serious health risks,including potentially fatal arrhythmias.The human ether-à-go-go related gene(hERG)potassium channel,as one of the primary targets of cardiotoxicity,has garnered widespread attention.Traditional cardiotoxicity testing methods are expensive and time-consuming,making computational virtual screening a suitable alternative.In this study,we employed machine learning techniques utilizing molecular fingerprints and descriptors to predict the cardiotoxicity of compounds,with the aim of improving prediction accuracy and efficiency.We used four types of molecular fingerprints and descriptors combined with machine learning and deep learning algorithms,including Gaussian naive Bayes(NB),random forest(RF),support vector machine(SVM),K-nearest neighbors(KNN),eXtreme gradient boosting(XGBoost),and Transformer models,to build predictive models.Our models demonstrated advanced predictive performance.The best machine learning model,XGBoost Morgan,achieved an accuracy(ACC)value of 0.84,and the deep learning model,Transformer_Morgan,achieved the best ACC value of 0.85,showing a high ability to distinguish between toxic and non-toxic compounds.On an external independent validation set,it achieved the best area under the curve(AUC)value of 0.93,surpassing ADMETlab3.0,Cardpred,and CardioDPi.In addition,we explored the integration of molecular descriptors and fingerprints to enhance model performance and found that ensemble methods,such as voting and stacking,provided slight improvements in model stability.Furthermore,the SHapley Additive exPlanations(SHAP)explanations revealed the relationship between benzene rings,fluorine-containing groups,NH groups,oxygen in ether groups,and cardiotoxicity,highlighting the importance of these features.This study not only improved the predictive accuracy of cardiotoxicity models but also promoted a more reliable and scientifically interpretable method for drug safety assessment.Using computational methods,this study facilitates a more efficient drug development process,reduces costs,and improves the safety of new drug candidates,ultimately benefiting medical and public health.
基金supported by the National Key Research and Development Program of China(2022YFB3305900)the Science and Technology Innovation Action Plan Computational Biology Program(24JS2830400)+1 种基金the Fundamental Research Funds for the Central Universities(222202517006)the Programme of Introducing Talents of Discipline to Universities(the 111 Project)(B17017).
文摘“A child receiving a single shot containing mRNA vaccines that protect against multiple diseases,all delivered with one lipid nanoparticle”—this is how Professor Drew Weissman,the 2023 Nobel laureate in Physiology or Medicine[1],described the potential of messenger RNA(mRNA)therapy in an interview with Forbes[2].In 2024,the Nobel Prize was again awarded to RNA researchers,this time to Victor Ambros and Gary Ruvkun for the discovery of microRNA and its role in post-transcriptional gene regulation[3],further underscoring the transformative capacity of RNA therapeutics in the 21st century healthcare.
基金supported from the Key R&D Program of Zhejiang(2025C02198)Zhejiang Provincial Administration of Traditional Chinese Medicine Co-construction Science and Technology Plan Project(GZY-ZJ-KJ-24083).
文摘Cancer therapy continues to face major challenges,including drug resistance,toxicity,and tumor heterogeneity,which highlight the need for multitarget strategies.This review examines the molecular compatibility theory in integrative oncology,which combines traditional Chinese medicine(TCM)with systems biology to address these limitations.TCM formulas,such as Banxia Xiexin decoction and Qiqin Huchang formula,contain bioactive compounds(e.g.,quercetin and berberine)that modulate interconnected pathways(phosphoinositide 3-kinase/protein kinase B and mitogen-activated protein kinase)and the tumor microenvironment,thereby promoting apoptosis,inhibiting angiogenesis,and regulating immune responses.The theory modernizes TCM’s“Jun-Chen-Zuo-Shi”principle by optimizing herb combinations through network pharmacology and omics technologies.For instance,Astragalus membranaceus(Fisch.)Bge.var.mongholicus(Bge.)Hsiao(Huang Qi)-Curcuma phaeocaulis Val.(E Zhu)pairs co-target hypoxia-inducible factor 1-alpha to suppress metastasis,while artificial intelligence-driven models predict synergistic interactions such as quercetin-cyclin-dependent kinase 1 inhibition.Clinical studies have shown improved outcomes;for instance,modified Banxia Xiexin decoction reduces chemotherapy-induced toxicity in gastric cancer,and Xihuang pill enhances immunotherapy via signal transducer and activator of transcription 3-programmed death-ligand 1 modulation.Despite these advances,challenges remain in standardization and mechanistic validation.Future research should prioritize single-cell sequencing,organoid models,and international collaboration to refine personalized therapies and translate TCM into evidence-based oncology.By integrating empirical knowledge with modern science,molecular compatibility theory provides a robust framework for multitarget drug development and the advancement of integrative cancer therapies.
基金supported by the Centrally Guided Local Science and Technology Development Project(2024ZYD0043).
文摘Artificial intelligence(AI)is revolutionizing the traditional paradigm of drug development at an unprecedented pace.With the rapid advancement of technologies such as deep learning and machine learning,AI has demonstrated substantial potential in various aspects of pharmaceutical research,including drug target identification,molecular design,and clinical trial optimization(Figure 1).Industry reports suggest that AI has the potential to reduce the drug development timeline from the conventional 10–15 years to 2–3 years,while also slashing development costs by billions of dollars.This article provides a comprehensive analysis of the current applications and future trends of AI in drug development and discovery,focusing on three dimensions:current hotspots,challenges,and future directions.
文摘Model-informed drug develop⁃ment(MIDD)is the application of a various math⁃ematical,statistical,and biological models to facilitate drug development,decision making and regulatory review.As a quantitative tool,MIDD approaches allow an integration of information obtained from non-clinical studies and clinical trials in a drug development program.General understandings of the underlying biology,patho⁃physiology,and pharmacology can also be incor⁃porated into the model.MIDD is centered on knowledge and inferences generated from inte⁃grated models of the physicochemical character⁃istics of a molecule,its disposition in the body,and its mechanism of action,and how the drug might affect a disease from both an efficacy and a safety perspective.MIDD approaches have the potential to significantly streamline drug develop⁃ment,by improving clinical trial efficiency,opti⁃mizing dose and regimen and waive unneces⁃sary clinical studies.This presentation will use cases studies to demonstrate how to apply MIDD in early phase of clinical trials.
文摘The therapeutic landscape of metastatic colorectal cancer(mCRC)has changed substantially with the emergence of new molecularly targeted agents(MTA)usedas single agents or alongside standard chemotherapy.The use of these MTAs extended the overall survival ofpatients with mCRC to a level that current chemotherapeutics alone could not achieve.In addition,improvement in surgical techniques and ablation modalities offer cure to a limited subset of patients with mCRC andMTAs have been found to have a significant role heretoo,as they aid resectability.However,for the majority of patients,mCRC remains an invariably incurabledisease necessitating continued courses of combinedtreatment modalities.During the course of these treatments,either cytotoxic or biological,cancer cells maintain their ability to acquire mitogenic mutations whichrender them resistant to treatment.Key challengesremain to identify appropriate subsets of patients whowill most likely benefit from these new MTAs and effectively select these based on validated biomarkers.Moreover,better knowledge of the biology of colorectal cancer and the mechanisms via which it bypasses blockade of known signalling pathways will help us design better and more rational sequencing of these treatments,so that we can maximise the survivorship of mCRC patients.This review outlines treatment strategies for known molecular alterations with new MTAs and highlights some promising strategies.
文摘Alzheimer＇s disease （AD） is the most frequent cause of dementia in the western world. In clinical terms, AD is characterized by progres- sive cognitive decline that usually begins with memory impairment. As the disease progresses, AD inevitably affects all intellectual functions including executive functions, leading to complete dependence for basic activities of daily life and premature death.
文摘Drug development in oncology is undergoing a substantial shift nowadays. The drivers for this are multi-factorial. On the one side, drug development is performed more rationally than ever, profiting from the scientific advances in molecular biology in general and the elucidation of the various ＂omes＂ from genome to metabolome in particular.
文摘Since President Obama announced the Precision Medicine Initiative from a national strategy perspective in his State of the Union address,precision medicine has rapidly become a world-wide hotspot and drawn global attention in the medical field.Precision medicine aims at applying genetic information of individual diseases to guide his or her diagnosis and treatment.
文摘Modern drugs have changed epilepsy,which affects people of all ages.However,for young people with epilepsy,the framework of drug development has stalled.In the wake of the thalidomide catastrophe,the misconception emerged that for people<18 years of age drugs,including antiseizure medications(ASMs),need separate proof of efficacy and safety,overall called"pediatric drug development".For ASMs,this has changed to some degree.Authorities now accept that ASMs are effective in<18 years as well,but they still require"extrapolation of efficacy,"as if minors were another species.As a result,some of the pediatric clinical epilepsy research over the past decades was unnecessary.Even more importantly,this has hampered research on meaningful research goals.We do not need to confirm that ASMs work before as they do after the 18th birthday.Instead,we need to learn how to prevent brain damage in young patients by preventing seizures and optimize ASMs’uses.Herein we discuss how to proceed in this endeavor.
文摘With the rapid development of modern science and technology, traditional randomized controlled trials have become insufficient to meet current scientific research needs, particularly in the field of clinical research. The emergence of real-world data studies, which align more closely with actual clinical evidence, has garnered significant attention in recent years. The following is a brief overview of the specific utilization of real-world data in drug development, which often involves large sample sizes and analyses covering a relatively diverse population without strict inclusion and exclusion criteria. Real-world data often reflects real clinical practice: treatment options are chosen according to the actual conditions and willingness of patients rather than through random assignment. Analysis based on real-world data also focuses on endpoints highly relevant to clinical benefits and the quality of life of patients. The booming big data technology supports the utilization of real-world data to accelerate new drug development, serving as an important supplement to traditional clinical trials.
文摘Objective To identify the critical risks in the process of innovative drug research and development,and to provide reference for improving the efficiency of innovative drug development and risk control in China.Methods Expert investigation and analytic hierarchy process were used to determine the weights of different risks.Results and Conclusion The research and analysis results showed that the risks at different stages of development had different effects on the success rate of drug development,among which the risk at the drug discovery stage influenced the most.In the drug discovery stage,inappropriate target selection had the greatest impact on the success rate of drug development.The lack of appropriate cell tissue or animal models had the greatest impact on the success rate of drug development from the discovery of a compound to the application for clinical trials.The difference in changes between nonclinical and clinical studies had the greatest impact on the success rate of drug development from early clinical studies to pivotal clinical studies.Incorrect dose selection had the greatest impact on the success rate of drug development from pivotal clinical studies to marketing authorization applications.The biggest impact from the marketing authorization application to the approval stage was inadequate communication with regulators.After investigating the weight of risk factors in the process of innovative drug development based on scientific methods,a new perspective for the risk control of new drug development and improving the research and development efficiency is provided.
基金supported by the Key Project of the National Medical Products Administration for the Construction of the Drug Regulatory Science System (RS2024Z003).
文摘advancements in first-in-class therapies and breakthrough technologies.The United States has maintained its leadership in first-in-class therapies and breakthrough technologies,driven by advanced regulatory pathways,significant multinational corporation investments,a robust Research and Development(R&D)workforce,and continuous technological innovation.Additionally,global impact of the Food and Drug Administration(FDA)is further amplified through collaborations like Project Orbis,which facilitates simultaneous reviews of cancer treatments by multiple regulatory authorities worldwide.Europe,while historically strong,faces growing challenges in maintaining its competitive edge,particularly due to protracted regulatory timelines and complex coordination among its member states.In this competitive global environment,China has rapidly transformed from a generics-dominated market to a key player in innovative drug development.This article reviews China’s progress in innovative drug R&D from 2019 to 2023,emphasizing regulatory modernization,clinical trial advancements,and the emergence of novel therapies.By comparing China’s developments with above global counterparts,this review highlights the country’s achievements in regulatory efficiency,clinical trial progress,and the development of innovative therapies such as biologics and cell and gene therapies.
基金supported by the National Natural Science Foundation of China(82272067).
文摘The unique characteristics of the deep space environment,microgravity,cosmic radiation,and extreme temperature fluctuations,are emerging as major driving forces for pharmaceutical innovation.These factors provide new avenues for optimizing drug formulations,improving crystal structure quality,and accelerating the discovery of therapeutic targets.Advances in deep space research not only help overcome critical bottlenecks in terrestrial drug development but also promote progress in structure-based drug design and deepen understanding of cellular stress-response mechanisms.Current progress in space-based pharmaceutical research primarily includes the study of disease mechanisms under microgravity,protein crystallization in microgravity,and drug development utilizing deep space radiation and resources.However,the operational complexity,high costs,and limited data reproducibility of space experiments remain key challenges hindering widespread application.Looking ahead,with the integration of automation,artificial intelligence analysis,and on-orbit manufacturing,deep space drug development is expected to achieve greater scalability and precision,opening a new frontier in biopharmaceutical science.
基金supported by the National Program for Support of Top-notch Young Professionals(Grant No.0106514050 to Yonghui Zhang,China)the National Natural Science Foundation of China(Grant Nos.82273811 and U22A20380 to Yonghui Zhang)+1 种基金the National Key Research and Development Program of China(Grant No.2021YFA0910500 to Yonghui Zhang)TongjiRongcheng Center for Biomedicine,Huazhong University of Science and Technology。
文摘Viruses constitute a significant group of pathogens that have caused numerous fatalities and substantial economic losses in recent years,particularly with the emergence of coronaviruses.While the impact of SARS-CoV-2 appears to be diminishing in daily life,only a limited number of drugs have received approval or emergency use authorization for its treatment.Given the high mutation rate of viral genomes,host-directed agents(HDAs)have emerged as a preferred choice due to their broad applicability and lasting effectiveness.In contrast to direct-acting antivirals(DAAs),HDAs offer several advantages,including broad-spectrum antiviral activities,potential efficacy against future emerging viruses,and a lower likelihood of inducing drug resistance.In our review article,we have synthesized known host-directed antiviral targets that span diverse cellular pathways and mechanisms,shedding light on the intricate interplay between host cells and viruses.Additionally,we have provided a brief overview of the development of HDAs based on these targets.We aim for this comprehensive analysis to offer valuable perspectives and insights that can guide future antiviral research and drug development efforts.
基金supported by the National Key Research and Development Program of China(2023YFC2508500)Beijing Municipal Health Commission(Beijing Demonstration Research Ward BCRW20200303)+1 种基金the National Natural Science Foundation of China(82272951 and 82272953)the Chinese Academy of Medical Sciences(2022-I2M-C&T-B-070).
文摘Rare diseases continue to pose a formidable public health challenge with lack or absence of effective treatments,demonstrating an immense need for rare disease drugs.However,the development of rare disease drugs remains uneven globally due to disparities in resource allocation,policy support,and medical infrastructure[1].Compared with other regions such as the USA and the EU,China exhibits distinct needs related to its particular disease spectrum,incidence,prevalence,genetic backgrounds,aetiology,and clinical practices[2].
基金supported by the National Key Research and Development Program of China(2021YFE0206000)National Natural Science Foundation of China(Nos.22177086,81973334,and 22477093)+2 种基金STI2030-Major Projects(No.2021ZD0204004,China)Major Basic Research Project of the Natural Science Foundation of the Jiangsu Higher Education Institutes(No.22KJA350004,China)Priority Academic Program Development of the Jiangsu Higher Education Institutes(PAPD).
文摘Sigma-1 receptor(σ1R)has become a focus point of drug discovery for central nervous system(CNS)diseases.A series of novel 1-phenylethan-1-one O-(2-aminoethyl)oxime derivatives were synthesized.In vitro biological evaluation led to the identification of 1a,14a,15d and 16d as the most high-affinity(K_(i)<4 nmol/L)and selectiveσ1R agonists.Among these,15d,the most metabolically stable derivative exhibited high selectivity forσ1R in relation toσ_(2)R and 52 other human targets.In addition to low CYP450 inhibition and induction,15d also exhibited high brain permeability and excellent oral bioavailability.Importantly,15d demonstrated effective antipsychotic potency,particularly for alleviating negative symptoms and improving cognitive impairment in experimental animal models,both of which are major challenges for schizophrenia treatment.Moreover,15d produced no significant extrapyramidal symptoms,exhibiting superior pharmacological profiles in relation to current antipsychotic drugs.Mechanistically,15d inhibited GSK3βand enhanced prefrontal BDNF expression and excitatory synaptic transmission in pyramidal neurons.Collectively,these in vivo proof-of-concept findings provide substantial experimental evidence to demonstrate that modulatingσ1R represents a potential new therapeutic approach for schizophrenia.The novel chemical entity along with its favorable drug-like and pharmacological profile of 15d renders it a promising candidate for treating schizophrenia.
文摘In vitro 3D cancer spheroids (tumoroids) exhibit a drug resistance profile similar to that found in solid tumors. 3D spheroid culture methods recreate more physiologically relevant microenvironments for cells. Therefore, these models are more appropriate for cancer drug screening. We have recently developed a protocol for MCF-7 cell spheroid culture, and used this method to test the effects of different types of drugs on this estrogen-dependent breast cancer cell spheroid. Our results demonstrated that MCF-7 cells can grow spheroid in medium using a low attachment plate. We managed to grow one spheroid in each well, and the spheroid can grow over a month, the size of the spheroid can grow over a hundred times in volume. Our targeted drug experimental results suggest that estrogen sulfotransferase, steroid sulfatase, and G protein-coupled estrogen receptor may play critical roles in MCF-7 cell spheroid growth, while estrogen receptors α and β may not play an essential role in MCF-7 spheroid growth. Organoids are the miniatures of in vivo tissues and reiterate the in vivo microenvironment of a specific organ, best fit for the in vitro studies of diseases and drug development. Tumoroid, developed from cancer cell lines or patients’ tumor tissue, is the best in vitro model of in vivo tumors. 3D spheroid technology will be the best future method for drug development of cancers and other diseases. Our reported method can be developed clinically to develop personalized drugs when the patient’s tumor tissues are used to develop a spheroid culture for drug screening.
基金supported by the Twelfth Five-Year National Science and Technology Major Project(No.201409304-307-301)
文摘Over the past 30 years, China has significantly improved the drug development environment by establishing a series of policies for the regulation of new drug approval. The regulatory system for new drug evaluation and registration in China was gradually developed in accordance with international standards. The approval and registration of TCM in China became as strict as those of chemical drugs and biological products. In this review, TCM-based new drug discovery and development are introduced according to the TCM classification of nine categories.
