Extensive structure-activity relationships(SARs)study of JND3229 was conducted to yield a series of new reve rsible 2-oxo-3,4-dihydropyrimido[4,5-d]pyrimidine privileged scaffold as EGFRC797 S inhibitors.One of the mo...Extensive structure-activity relationships(SARs)study of JND3229 was conducted to yield a series of new reve rsible 2-oxo-3,4-dihydropyrimido[4,5-d]pyrimidine privileged scaffold as EGFRC797 S inhibitors.One of the most potent compound 6 i potently suppressed EGFRL858 R/T790 M/C797 S kinase with an IC50 value of 3.1 nmol/L,and inhibited the proliferation of BaF3 cells harboring EGFRL858 R/T790 M/C797 S and EGFR19 D/T790 M/C797 S mutants with IC50 values of 290 nmol/L and 316 nmol/L,respectively.Further,6 i dose-dependently induced suppression of the phosphorylation of EGFRL858 R/T790 M/C797 S and EGFR19 D/T790 M/C797 S in BaF3 cells.Compound 6 i may serve as a promising lead compound for further drug discovery overcoming the acquired resistance of non-small cell lung cancer(NSCLC)patients.展开更多
The p21-activated kinase 4(PAK4),a key regulator of malignancy,is negatively correlated with immune infiltration and has become an emergent drug target of cancer therapy.Given the lack of high efficacy PAK4 inhibitors...The p21-activated kinase 4(PAK4),a key regulator of malignancy,is negatively correlated with immune infiltration and has become an emergent drug target of cancer therapy.Given the lack of high efficacy PAK4 inhibitors,we herein reported the identification of a novel inhibitor 13 bearing a tetrahydrobenzofuro[2,3-c]pyridine tricyclic core and possessing high potency against MIA PaCa-2 and Pan02 cell lines with IC_(50) values of 0.38 and 0.50 mmol/L,respectively.This compound directly binds to PAK4 in a non-ATP competitive manner.In the mouse Pan02 model,compound 13 exhibited significant tumor growth inhibition at a dose of 100 mg/kg,accompanied by reduced levels of PAK4 and its phosphorylation together with immune infiltration in mice tumor tissue.Overall,compound 13 is a novel allosteric PAK4 inhibitor with a unique tricyclic structural feature and high potency both in vitro and in vivo,thus making it worthy of further exploration.展开更多
Third-generation EGFR tyrosine kinase inhibitors(TKIs),exemplified by osimertinib,have demonstrated promising clinical efficacy in the treatment of non-small cell lung cancer(NSCLC).Our previous work has identified AS...Third-generation EGFR tyrosine kinase inhibitors(TKIs),exemplified by osimertinib,have demonstrated promising clinical efficacy in the treatment of non-small cell lung cancer(NSCLC).Our previous work has identified ASK120067 as a novel third-generation EGFR TKI with remarkable antitumor effects that has undergone New Drug Application(NDA)submission in China.Despite substantial progress,acquired resistance to EGFR-TKIs remains a significant challenge,impeding the long-term effectiveness of therapeutic approaches.In this study,we conducted a comprehensive investigation utilizing high-throughput proteomics analysis on established TKI-resistant tumor models,and found a notable upregulation of branched-chain amino acid transaminase 1(BCAT1)expression in both osimertinib-and ASK120067-resistant tumors compared with the parental TKI-sensitive NSCLC tumors.Genetic depletion or pharmacological inhibition of BCAT1 impaired the growth of resistant cells and partially re-sensitized tumor cells to EGFR TKIs.Mechanistically,upregulated BCAT1 in resistant cells reprogrammed branched-chain amino acid(BCAA)metabolism and promoted alpha ketoglutarate(α-KG)-dependent demethylation of lysine 27 on histone H3(H3K27)and subsequent transcriptional derepression of glycolysis-related genes,thereby enhancing glycolysis and promoting tumor progression.Moreover,we identified WQQ-345 as a novel BCAT1 inhibitor exhibiting antitumor activity both in vitro and in vivo against TKI-resistant lung cancer with high BCAT1 expression.In summary,our study highlighted the crucial role of BCAT1 in mediating resistance to third-generation EGFR-TKIs through epigenetic activation of glycolysis in NSCLC,thereby supporting BCAT1 as a promising therapeutic target for the treatment of TKI-resistant NSCLC.展开更多
Oncogenes are critical factors in tumorigenesis of diverse cancer types and play essential roles in tumor immune escape.Mutations in Kirsten rat sarcoma viral oncogene homolog(KRAS)and epidermal growth factor receptor...Oncogenes are critical factors in tumorigenesis of diverse cancer types and play essential roles in tumor immune escape.Mutations in Kirsten rat sarcoma viral oncogene homolog(KRAS)and epidermal growth factor receptor(EGFR)are among the most frequent gain-of-function alterations[1].After many years of in-depth research,inhibitors targeting EGFR or KRAS mutations have been successfully developed,however,their clinical benefit is relatively limited,and they will inevitably encounter the challenge of drug resistance.The emergence of resistance is attributed to secondary mutations in driver genes and other complicated factors.展开更多
Glioblastoma(GBM)is the most common and aggressive malignant brain tumor in adults and is poorly controlled.Previous studies have shown that both macrophages and angiogenesis play significant roles in GBM progression,...Glioblastoma(GBM)is the most common and aggressive malignant brain tumor in adults and is poorly controlled.Previous studies have shown that both macrophages and angiogenesis play significant roles in GBM progression,and co-targeting of CSF1R and VEGFR is likely to be an effective strategy for GBM treatment.Therefore,this study developed a novel and selective inhibitor of CSFIR and VEGFR,SYHA1813,possessing potent antitumor activity against GBM.SYHA1813 inhibited VEGFR and CSFIR kinase activities with high potency and selectivity and thus blocked the cell viability of HUVECs and macrophages and exhibited anti-angiogenetic effects both in vitro and in vivo.SYHA1813 also displayed potent in vivo antitumor activity against GBM in immune-competent and immune-deficient mouse models,including temozolomide(TMZ)insensitive tumors.Notably,SYHA1813 could penetrate the blood-brain barrier(BBB)and prolong the survival time of mice bearing intracranial GBM xenografts.Moreover,SYHA1813 treatment resulted in a synergistic antitumor efficacy in combination with the PD-1 antibody.As a clinical proof of concept,SYHA1813 achieved confirmed responses in patients with recurrent GBM in an ongoing first-in-human phase I trial.The data of this study support the rationale for an ongoing phase I clinical study(ChiCTR2100045380).展开更多
Camptothecin(CPT)is a natural topoisomerase I inhibitor with powerful antineoplastic activity against colorectal,breast,lung and ovarian cancers.To discover more potent antitumor agents,a series of new CPT derivatives...Camptothecin(CPT)is a natural topoisomerase I inhibitor with powerful antineoplastic activity against colorectal,breast,lung and ovarian cancers.To discover more potent antitumor agents,a series of new CPT derivatives were synthesized utilizing click chemistry.All compounds were assessed for cytotoxicity against A549,HCT-116,HT-29,LoVo,MDA-MB-231 cell lines,and some compounds exhibited good in vitro potency.Furthermore,all compounds kept or enhanced Topo I inhibition.展开更多
基金financial support from the National Natural Science Foundation of China(Nos.81922062,81874285 and 81673285)Guangdong International Science and TechnologyCooperation Project(No.2018A050506043)+1 种基金Guangzhou City Key Laboratory of Precision Chemical Drug Development(No.201805010007)Institutes for Drug Discovery and Development of Chinese Academy of Science(No.CASIMM0120185006)。
文摘Extensive structure-activity relationships(SARs)study of JND3229 was conducted to yield a series of new reve rsible 2-oxo-3,4-dihydropyrimido[4,5-d]pyrimidine privileged scaffold as EGFRC797 S inhibitors.One of the most potent compound 6 i potently suppressed EGFRL858 R/T790 M/C797 S kinase with an IC50 value of 3.1 nmol/L,and inhibited the proliferation of BaF3 cells harboring EGFRL858 R/T790 M/C797 S and EGFR19 D/T790 M/C797 S mutants with IC50 values of 290 nmol/L and 316 nmol/L,respectively.Further,6 i dose-dependently induced suppression of the phosphorylation of EGFRL858 R/T790 M/C797 S and EGFR19 D/T790 M/C797 S in BaF3 cells.Compound 6 i may serve as a promising lead compound for further drug discovery overcoming the acquired resistance of non-small cell lung cancer(NSCLC)patients.
基金support from the China National Innovation of Science and Technology-2030(Program of Brain Science and Brain-Inspired Intelligence Technology,2021ZD0204004)the National Natural Science Foundation of China(Grants Nos.82273767,82073073,82122045,and 82273948)+3 种基金the Major Projects for Shanghai Zhang jiang National Independent Innovation of China(ZJ2021-ZD-007)Innovative research team of high-level local universities in Shanghai(SHSMU-ZDCX20210802,China)the Project of Shanghai Institute of Materia Medica,CAS(SIMM0120231001,China)the High-level Innovative Research Institute,Department of Science and Technology of Guangdong Province(2021B0909050003,China).
文摘The p21-activated kinase 4(PAK4),a key regulator of malignancy,is negatively correlated with immune infiltration and has become an emergent drug target of cancer therapy.Given the lack of high efficacy PAK4 inhibitors,we herein reported the identification of a novel inhibitor 13 bearing a tetrahydrobenzofuro[2,3-c]pyridine tricyclic core and possessing high potency against MIA PaCa-2 and Pan02 cell lines with IC_(50) values of 0.38 and 0.50 mmol/L,respectively.This compound directly binds to PAK4 in a non-ATP competitive manner.In the mouse Pan02 model,compound 13 exhibited significant tumor growth inhibition at a dose of 100 mg/kg,accompanied by reduced levels of PAK4 and its phosphorylation together with immune infiltration in mice tumor tissue.Overall,compound 13 is a novel allosteric PAK4 inhibitor with a unique tricyclic structural feature and high potency both in vitro and in vivo,thus making it worthy of further exploration.
基金supported by grants from the National Natural Science Foundation of China(82273948 and 81903638)High-level Innovative Research Institute(2021B0909050003)+5 种基金State Key Laboratory of Drug Research(SKLDR-2023-TT-01 and SIMM2205KF-09)Lingang Laboratory(LG202103-02-02)Institutes for Drug Discovery and Development,Chinese Academy of Sciences(CASIMM0120225003-1 and-2)Guangdong Basic and Applied Basic Research Foundation(2021A1515010197 and 2023A1515012259)Zhongshan Municipal Natural Science Foundation(200805173640573 and 210730214049987)Project of Shanghai Institute of Materia Medica,Chinese Academy of Sciences(SIMM0120231001).
文摘Third-generation EGFR tyrosine kinase inhibitors(TKIs),exemplified by osimertinib,have demonstrated promising clinical efficacy in the treatment of non-small cell lung cancer(NSCLC).Our previous work has identified ASK120067 as a novel third-generation EGFR TKI with remarkable antitumor effects that has undergone New Drug Application(NDA)submission in China.Despite substantial progress,acquired resistance to EGFR-TKIs remains a significant challenge,impeding the long-term effectiveness of therapeutic approaches.In this study,we conducted a comprehensive investigation utilizing high-throughput proteomics analysis on established TKI-resistant tumor models,and found a notable upregulation of branched-chain amino acid transaminase 1(BCAT1)expression in both osimertinib-and ASK120067-resistant tumors compared with the parental TKI-sensitive NSCLC tumors.Genetic depletion or pharmacological inhibition of BCAT1 impaired the growth of resistant cells and partially re-sensitized tumor cells to EGFR TKIs.Mechanistically,upregulated BCAT1 in resistant cells reprogrammed branched-chain amino acid(BCAA)metabolism and promoted alpha ketoglutarate(α-KG)-dependent demethylation of lysine 27 on histone H3(H3K27)and subsequent transcriptional derepression of glycolysis-related genes,thereby enhancing glycolysis and promoting tumor progression.Moreover,we identified WQQ-345 as a novel BCAT1 inhibitor exhibiting antitumor activity both in vitro and in vivo against TKI-resistant lung cancer with high BCAT1 expression.In summary,our study highlighted the crucial role of BCAT1 in mediating resistance to third-generation EGFR-TKIs through epigenetic activation of glycolysis in NSCLC,thereby supporting BCAT1 as a promising therapeutic target for the treatment of TKI-resistant NSCLC.
基金This research was supported by grants from the Natu-ral Science Foundation of China for Innovation Research Group(81821005)the National Natural Science Founda-tionofChina(82273948,81573271and81903638)+3 种基金High-level Innovative Research Institute(2021B0909050003)State Key Laboratory of Drug Research(SKLDR-2023-TT-01 and SIMM2205KF-09)Lingang Laboratory(LG202103-02-02)Institutes for Drug Discovery and Development,Chinese Academy of Sciences(CASIMM0120225003-1 and-2).
文摘Oncogenes are critical factors in tumorigenesis of diverse cancer types and play essential roles in tumor immune escape.Mutations in Kirsten rat sarcoma viral oncogene homolog(KRAS)and epidermal growth factor receptor(EGFR)are among the most frequent gain-of-function alterations[1].After many years of in-depth research,inhibitors targeting EGFR or KRAS mutations have been successfully developed,however,their clinical benefit is relatively limited,and they will inevitably encounter the challenge of drug resistance.The emergence of resistance is attributed to secondary mutations in driver genes and other complicated factors.
基金supported by grants from the Natural Science Foundation of China for Innovation Research Group(81821005)the National Natural Science Foundation of China(82273948 and 81573271)+2 种基金the"Personalized Medicines,Molecular Signaturebased Drug Discovery and Development",Strategic Priority Research Program of the Chinese Academy of Sciences(XDA12020203 and XDA12020228,China)the National Science&Technology Major Project"Key New Drug Creation and Manufacturing Program",China(2018ZX09711002-011-016)the Youth Innovation Promotion Association of CAS(2018324,China).
文摘Glioblastoma(GBM)is the most common and aggressive malignant brain tumor in adults and is poorly controlled.Previous studies have shown that both macrophages and angiogenesis play significant roles in GBM progression,and co-targeting of CSF1R and VEGFR is likely to be an effective strategy for GBM treatment.Therefore,this study developed a novel and selective inhibitor of CSFIR and VEGFR,SYHA1813,possessing potent antitumor activity against GBM.SYHA1813 inhibited VEGFR and CSFIR kinase activities with high potency and selectivity and thus blocked the cell viability of HUVECs and macrophages and exhibited anti-angiogenetic effects both in vitro and in vivo.SYHA1813 also displayed potent in vivo antitumor activity against GBM in immune-competent and immune-deficient mouse models,including temozolomide(TMZ)insensitive tumors.Notably,SYHA1813 could penetrate the blood-brain barrier(BBB)and prolong the survival time of mice bearing intracranial GBM xenografts.Moreover,SYHA1813 treatment resulted in a synergistic antitumor efficacy in combination with the PD-1 antibody.As a clinical proof of concept,SYHA1813 achieved confirmed responses in patients with recurrent GBM in an ongoing first-in-human phase I trial.The data of this study support the rationale for an ongoing phase I clinical study(ChiCTR2100045380).
基金This work was supported by the grants of The National Natural Science Foundation of China(Nos.81172936,21102046),and grants of The Fundamental Research Funds for the Central Universities.We also thank the Laboratory of Organic Functional Molecules,the Sino-French Institute of ECNU for support.
文摘Camptothecin(CPT)is a natural topoisomerase I inhibitor with powerful antineoplastic activity against colorectal,breast,lung and ovarian cancers.To discover more potent antitumor agents,a series of new CPT derivatives were synthesized utilizing click chemistry.All compounds were assessed for cytotoxicity against A549,HCT-116,HT-29,LoVo,MDA-MB-231 cell lines,and some compounds exhibited good in vitro potency.Furthermore,all compounds kept or enhanced Topo I inhibition.
