Predicting and overcoming resistance to CDK9 inhibitors for cancer therapy

作     者：Chen Hu Lijuan Shen Fengming Zou Yun Wu Beilei Wang Aoli Wang Chao Wu Li Wang Jing Liu Wenchao Wang Qingsong Liu Chen Hu;Lijuan Shen;Fengming Zou;Yun Wu;Beilei Wang;Aoli Wang;Chao Wu;Li Wang;Jing Liu;Wenchao Wang;Qingsong Liu

作者机构：Anhui Province Key Laboratory of Medical Physics and TechnologyInstitute of Health and Medical TechnologyHefei Institutes of Physical ScienceChinese Academy of SciencesHefei 230031China University of Science and Technology of ChinaHefei 230026China Hefei Cancer HospitalChinese Academy of SciencesHefei 230031China Tarapeutics Science Inc.Bengbu 233000China Precision Medicine Research Laboratory of Anhui ProvinceHefei 230088China 

出 版 物：《药学学报:英文版》 (Acta Pharmaceutica Sinica B)

年 卷 期：2023年第13卷第9期

页      面：3694-3707页

核心收录：

学科分类：1007[医学-药学(可授医学、理学学位)] 1006[医学-中西医结合] 100706[医学-药理学] 100602[医学-中西医结合临床] 10[医学] 

基　　金：supported by the National Natural Science Foundation of China(Grant Nos.81903650,32171479,82103976) the Natural Science Foundation of Anhui Province(Grant Nos.2008085MH274,2108085QH377,China) the Collaborative Innovation Program of Hefei Science Center,CAS(Grant No.2021HSC-CIP014,China) the CASHIPS Director’s Found(Grant Nos.YZJJZX202011,YZJJ2021QN38,China) supported by the High Magnetic Field Laboratory of Anhui Province 

主　　题：Acquired resistance mutations CDK9 inhibitors Transcription Single nucleotide polymorphisms BAY1251152 

摘      要：Abnormally activated CDK9 participates in the super-enhancer mediated transcription of short-lived proteins required for cancer cell *** CDK9 has shown potent anti-tumor activity in clinical trials among different ***,the study and knowledge on drug resistance to CDK9 inhibitors are very *** this study,we established an AML cell line with acquired resistance to a highly selective CDK9 inhibitor *** genomic sequencing,we identified in the kinase domain of CDK9 a mutation L156F,which is also a coding SNP in the CDK9 *** knocking in L156F into cancer cells using CRISPR/Cas9,we found that single CDK9 L156F could drive the resistance to CDK9 inhibitors,not only ATP competitive inhibitor but also PROTAC ***,CDK9 L156F disrupts the binding with inhibitors due to steric hindrance,further,the mutation affects the thermal stability and catalytic activity of CDK9 *** overcome the drug resistance mediated by the CDK9-L156F mutation,we discovered a compound,IHMT-CDK9-36 which showed potent inhibition activity both for CDK9 WT and L156F ***,we report a novel resistance mechanism for CDK9 inhibitors and provide a novel chemical scaffold for the future development of CDK9 inhibitors.