Dysregulation of histone deacetylases(HDACs) is closely related to tumor development and progression. As promising anticancer targets, HDACs have gained a great deal of research interests and two decades of effort has...Dysregulation of histone deacetylases(HDACs) is closely related to tumor development and progression. As promising anticancer targets, HDACs have gained a great deal of research interests and two decades of effort has led to the approval of five HDAC inhibitors(HDACis). However, currently traditional HDACis, although effective in approved indications, exhibit severe off-target toxicities and low sensitivities against solid tumors, which have urged the development of next-generation of HDACi. This review investigates the biological functions of HDACs, the roles of HDACs in oncogenesis, the structural features of different HDAC isoforms, isoform-selective inhibitors, combination therapies, multitarget agents and HDAC PROTACs. We hope these data could inspire readers with new ideas to develop novel HDACi with good isoform selectivity, efficient anticancer effect, attenuated adverse effect and reduced drug resistance.展开更多
Encoded by PTPN11,the SHP2(Src homology-2 domain-containing protein tyrosine phosphatase-2)is widely recognized as a carcinogenic phosphatase.As a promising anti-cancer drug target,SHP2 regulates many signaling pathwa...Encoded by PTPN11,the SHP2(Src homology-2 domain-containing protein tyrosine phosphatase-2)is widely recognized as a carcinogenic phosphatase.As a promising anti-cancer drug target,SHP2 regulates many signaling pathways such as RAS-RAF-ERK,PI3 K-AKT and JAK-STAT.Meanwhile,SHP2 plays a significant role in regulating immune cell function in the tumor microenvironment.Heretofore,five SHP2 allosteric inhibitors have been recruited in clinical studies for the treatment of cancer.Most recently,studies have proved the therapeutic potential of SHP2 inhibitor in overcoming drug resistance of kinase inhibitors and programmed cell death-1(PD-1)blockade.Herein,we review the structure,function and small molecular inhibitors of SHP2,and highlight recent progress in overcoming drug resistance using SHP2 inhibitor.We hope this review would facilitate the future clinical development of SHP2 inhibitors.展开更多
基金supported by the National Natural Science Foundation of China (81874288, 82003590 and 92053105)the Natural Science Foundation of Shandong Province (ZR2020QH342, China)+1 种基金the Key Project of Natural Science Foundation of Anhui Province for College Scholar (2022AH051216, China)Scientific Research Project of Anhui Provincial Health Commission (AHWJ2022b005, China)。
文摘Dysregulation of histone deacetylases(HDACs) is closely related to tumor development and progression. As promising anticancer targets, HDACs have gained a great deal of research interests and two decades of effort has led to the approval of five HDAC inhibitors(HDACis). However, currently traditional HDACis, although effective in approved indications, exhibit severe off-target toxicities and low sensitivities against solid tumors, which have urged the development of next-generation of HDACi. This review investigates the biological functions of HDACs, the roles of HDACs in oncogenesis, the structural features of different HDAC isoforms, isoform-selective inhibitors, combination therapies, multitarget agents and HDAC PROTACs. We hope these data could inspire readers with new ideas to develop novel HDACi with good isoform selectivity, efficient anticancer effect, attenuated adverse effect and reduced drug resistance.
基金supported by National Natural Science Foundation of China(Grant No.81874288,92053105 and 82003590)Natural Science Foundation of Shandong Province(ZR2020QH342,China)the Young Scholars Program of Shandong University(China)。
文摘Encoded by PTPN11,the SHP2(Src homology-2 domain-containing protein tyrosine phosphatase-2)is widely recognized as a carcinogenic phosphatase.As a promising anti-cancer drug target,SHP2 regulates many signaling pathways such as RAS-RAF-ERK,PI3 K-AKT and JAK-STAT.Meanwhile,SHP2 plays a significant role in regulating immune cell function in the tumor microenvironment.Heretofore,five SHP2 allosteric inhibitors have been recruited in clinical studies for the treatment of cancer.Most recently,studies have proved the therapeutic potential of SHP2 inhibitor in overcoming drug resistance of kinase inhibitors and programmed cell death-1(PD-1)blockade.Herein,we review the structure,function and small molecular inhibitors of SHP2,and highlight recent progress in overcoming drug resistance using SHP2 inhibitor.We hope this review would facilitate the future clinical development of SHP2 inhibitors.
