Discovery of selective CDK9 degraders with enhancing antiproliferative activity through PROTAC conversion

doi:10.1016/j.ejmech.2020.113091

	Discovery of selective CDK9 degraders with enhancing antiproliferative activity through PROTAC conversion
	Qiu, Xiaqiu 1,2; Li, Yuanqing 3; Yu, Bin 1,2; Ren, Jie 1,2; Huang, Huidan 4; Wang, Min 1,2; Ding, Hong 3; Li, Zhiyu 1,2; Wang, Jubo 1,2; Bian, Jinlei 1,2
刊名	EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
	2021-02-05
卷号	211 页码:11
关键词	CDK9 Antitumor PROTAC AML Degrader
ISSN号	0223-5234
DOI	10.1016/j.ejmech.2020.113091
通讯作者	Huang, Huidan(huanghuidan1989@163.com) ; Wang, Jubo() ; Bian, Jinlei(bianjl@cpu.edu.cn)
英文摘要	Cyclin-dependent kinase 9 (CDK9) is an increasingly important potential cancer treatment target. Nowadays, developing selective CDK9 inhibitors has been extremely challenging as its ATP-binding sites are similar with other CDKs. Here, we report that the CDK9 inhibitor BAY-1143572 is converted into a series of proteolysis targeting chimeras (PROTACs) which leads to several compounds inducing the degradation of CDK9 in acute myeloid leukemia cells at a low nanomolar concentration. In addition, the most potent PROTAC molecule B03 could inhibit cell growth more effectively than warhead alone, with little inhibition of other kinases. This enhanced antiproliferative activity is mediated by a slight increase in kinase inhibitory activity and an increase in the level of apoptosis induction. Moreover, B03 could induce the degradation of CDK9 in vivo. Our work provides evidence that B03 represents a lead for further development and that CDK9 degradation is a potential valuable therapeutic strategy in acute myeloid leukemia. (C) 2020 Elsevier Masson SAS. All rights reserved.
资助项目	National Natural Science Foundation of China[81872746] ; National Natural Science Foundation of China[81703347] ; Natural Science Foundation of Jiangsu Province of China[BK20170743] ; Natural Science Foundation of Jiangsu Province of China[BK20171393] ; National Innovation and Entrepreneurship Training Program For College Students[201910316030S] ; 'Double First-Class' University Project[CPU2018GY07] ; State Key Laboratory of Drug Research and Postgraduate Research & Practice Innovation Program of Jiangsu Province[KYCX18_0770]
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
WOS记录号	WOS:000639375500029
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/295866]
专题	中国科学院上海药物研究所
通讯作者	Huang, Huidan; Wang, Jubo; Bian, Jinlei
作者单位	1.China Pharmaceut Univ, Dept Med Chem, Sch Pharm, State Key Lab Nat Med, Nanjing 210009, Peoples R China 2.China Pharmaceut Univ, Dept Med Chem, Sch Pharm, Jiang Key Lab Drug Design & Optimizat, Nanjing 210009, Peoples R China 3.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, CAS Key Lab Receptor Res, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China 4.Wannan Med Coll, Sch Pharm, Wuhu 241002, Peoples R China
推荐引用方式 GB/T 7714	Qiu, Xiaqiu,Li, Yuanqing,Yu, Bin,et al. Discovery of selective CDK9 degraders with enhancing antiproliferative activity through PROTAC conversion[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2021,211:11.
APA	Qiu, Xiaqiu.,Li, Yuanqing.,Yu, Bin.,Ren, Jie.,Huang, Huidan.,...&Bian, Jinlei.(2021).Discovery of selective CDK9 degraders with enhancing antiproliferative activity through PROTAC conversion.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,211,11.
MLA	Qiu, Xiaqiu,et al."Discovery of selective CDK9 degraders with enhancing antiproliferative activity through PROTAC conversion".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 211(2021):11.