Predicting and overcoming resistance to CDK9 inhibitors for cancer therapy

doi:10.1016/j.apsb.2023.05.026

	Predicting and overcoming resistance to CDK9 inhibitors for cancer therapy
	Hua, Chen 3,5; Shena, Lijuan 4,5; Zoua, Fengming 3,5; Wua, Yun 3,5; Wanga, Beilei 3,5; Wanga, Aoli 3,5; Wud, Chao 2; Wanga, Li 3,5; Liua, Jing 3,4,5; Wanga, Wenchao 3,4,5
刊名	ACTA PHARMACEUTICA SINICA B
	2023-09-01
卷号	13
关键词	Acquired resistance mutations CDK9 inhibitors Transcription Single nucleotide polymorphisms BAY1251152
ISSN号	2211-3835
DOI	10.1016/j.apsb.2023.05.026
通讯作者	Liua, Jing(jingliu@hmfl.ac.cn) ; Wanga, Wenchao(wwcbox@hmfl.ac.cn) ; Liua, Qingsong(qsliu97@hmfl.ac.cn)
英文摘要	Abnormally activated CDK9 participates in the super-enhancer mediated transcription of short-lived proteins required for cancer cell survival. Targeting CDK9 has shown potent anti-tumor activ-ity in clinical trials among different cancers. However, the study and knowledge on drug resistance to CDK9 inhibitors are very limited. In this study, we established an AML cell line with acquired resistance to a highly selective CDK9 inhibitor BAY1251152. Through genomic sequencing, we identified in the kinase domain of CDK9 a mutation L156F, which is also a coding SNP in the CDK9 gene. By 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 degrader. Mech-anistically, CDK9 L156F disrupts the binding with inhibitors due to steric hindrance, further, the mutation affects the thermal stability and catalytic activity of CDK9 protein. To 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 mutant. Together, we report a novel resistance mechanism for CDK9 inhibitors and provide a novel chemical scaffold for the future development of CDK9 inhibitors.
资助项目	National Natural Science Foundation of China[81903650] ; National Natural Science Foundation of China[32171479] ; National Natural Science Foundation of China[82103976] ; Natural Science Foundation of Anhui Province, China[2008085MH274] ; Natural Science Foundation of Anhui Province, China[2108085QH377] ; Collaborative Innovation Program of Hefei Science Center, CAS, China[2021HSC-CIP014] ; CASHIPS Director's Found, China[YZJJZX202011] ; CASHIPS Director's Found, China[YZJJ2021QN38] ; High Magnetic Field Laboratory of Anhui Province
WOS关键词	CYCLIN-DEPENDENT KINASES ; POLYMORPHISMS
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	INST MATERIA MEDICA, CHINESE ACAD MEDICAL SCIENCES
WOS记录号	WOS:001077776900001
资助机构	National Natural Science Foundation of China ; Natural Science Foundation of Anhui Province, China ; Collaborative Innovation Program of Hefei Science Center, CAS, China ; CASHIPS Director's Found, China ; High Magnetic Field Laboratory of Anhui Province
内容类型	期刊论文
源URL	[http://ir.hfcas.ac.cn:8080/handle/334002/132525]
专题	中国科学院合肥物质科学研究院
通讯作者	Liua, Jing; Wanga, Wenchao; Liua, Qingsong
作者单位	1.Precis Med Res Lab Anhui Prov, Hefei 230088, Peoples R China 2.Tarapeut Sci Inc, Bengbu 233000, Peoples R China 3.Chinese Acad Sci, Hefei Canc Hosp, Hefei 230031, Peoples R China 4.Univ Sci & Technol China, Hefei 230026, Peoples R China 5.Chinese Acad Sci, Hefei Inst Phys Sci, Inst Hlth & Med Technol, Anhui Prov Key Lab Med Phys & Technol, Hefei 230031, Peoples R China
推荐引用方式 GB/T 7714	Hua, Chen,Shena, Lijuan,Zoua, Fengming,et al. Predicting and overcoming resistance to CDK9 inhibitors for cancer therapy[J]. ACTA PHARMACEUTICA SINICA B,2023,13.
APA	Hua, Chen.,Shena, Lijuan.,Zoua, Fengming.,Wua, Yun.,Wanga, Beilei.,...&Liua, Qingsong.(2023).Predicting and overcoming resistance to CDK9 inhibitors for cancer therapy.ACTA PHARMACEUTICA SINICA B,13.
MLA	Hua, Chen,et al."Predicting and overcoming resistance to CDK9 inhibitors for cancer therapy".ACTA PHARMACEUTICA SINICA B 13(2023).