Discovery of QCA570 as an Exceptionally Potent and Efficacious Proteolysis Targeting Chimera (PROTAC) Degrader of the Bromodomain and Extra-Terminal (BET) Proteins Capable of Inducing Complete and Durable Tumor Regression

doi:10.1021/acs.jmedchem.8b00506

	Discovery of QCA570 as an Exceptionally Potent and Efficacious Proteolysis Targeting Chimera (PROTAC) Degrader of the Bromodomain and Extra-Terminal (BET) Proteins Capable of Inducing Complete and Durable Tumor Regression
	Qin, Chong 2,3; Hu, Yang 2,3; Zhou, Bing2,3,8 ; Fernandez-Salas, Ester 1,2; Yang, Chao-Yie 2,3; Liu, Liu 2,3; McEachern, Donna 2,3; Przybranowski, Sally 2,3; Wang, Mi 2,3; Stuckey, Jeanne
刊名	JOURNAL OF MEDICINAL CHEMISTRY
	2018-08-09
卷号	61 期号:15 页码:6685-6704
ISSN号	0022-2623
DOI	10.1021/acs.jmedchem.8b00506
文献子类	Article
英文摘要	Proteins of the bromodomain and extra-terminal (BET) family are epigenetics "readers" and promising therapeutic targets for cancer and other human diseases. We describe herein a structure-guided design of [1,4]oxazepines as a new class of BET inhibitors and our subsequent design, synthesis, and evaluation of proteolysis-targeting chimeric (PROTAC) small-molecule BET degraders. Our efforts have led to the discovery of extremely potent BET degraders, exemplified by QCA570, which effectively induces degradation of BET proteins and inhibits cell growth in human acute leukemia cell lines even at low picomolar concentrations. QCAS70 achieves complete and durable tumor regression in leukemia xenograft models in mice at well-tolerated dose-schedules. QCA570 is the most potent and efficacious BET degrader reported to date.
资助项目	Breast Cancer Research Foundation[00000000] ; Prostate Cancer Foundation[00000000] ; National Cancer Institute, NIH[R01CA215758] ; University of Michigan Comprehensive Cancer Center support grant from the National Cancer Institute, NIH[P30 CA046592]
WOS关键词	RESISTANT PROSTATE-CANCER ; SMALL-MOLECULE PROTACS ; E3 UBIQUITIN LIGASE ; DRUG DISCOVERY ; INHIBITORS ; DEGRADATION ; DESIGN ; STRATEGY ; OPTIMIZATION ; INFLAMMATION
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	AMER CHEMICAL SOC
WOS记录号	WOS:000441484300015
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/279623]
专题	药物化学研究室
通讯作者	Wang, Shaomeng
作者单位	1.Univ Michigan, Sch Med, Dept Pathol, Ann Arbor, MI 48109 USA; 2.Univ Michigan, Sch Med, Rogel Canc Ctr, Ann Arbor, MI 48109 USA; 3.Univ Michigan, Sch Med, Dept Internal Med, Ann Arbor, MI 48109 USA; 4.Univ Michigan, Sch Med, Dept Pharmacol, Ann Arbor, MI 48109 USA; 5.Univ Michigan, Sch Med, Dept Med Chem, Ann Arbor, MI 48109 USA; 6.Univ Michigan, Coll Pharm, Life Sci Inst, Ann Arbor, MI 48109 USA; 7.Univ Michigan, Coll Pharm, Pharmacokinet Core, Ann Arbor, MI 48109 USA; 8.Chinese Acad Sci, Shanghai Inst Mat Med, Dept Med Chem, Shanghai 201203, Peoples R China
推荐引用方式 GB/T 7714	Qin, Chong,Hu, Yang,Zhou, Bing,et al. Discovery of QCA570 as an Exceptionally Potent and Efficacious Proteolysis Targeting Chimera (PROTAC) Degrader of the Bromodomain and Extra-Terminal (BET) Proteins Capable of Inducing Complete and Durable Tumor Regression[J]. JOURNAL OF MEDICINAL CHEMISTRY,2018,61(15):6685-6704.
APA	Qin, Chong.,Hu, Yang.,Zhou, Bing.,Fernandez-Salas, Ester.,Yang, Chao-Yie.,...&Wang, Shaomeng.(2018).Discovery of QCA570 as an Exceptionally Potent and Efficacious Proteolysis Targeting Chimera (PROTAC) Degrader of the Bromodomain and Extra-Terminal (BET) Proteins Capable of Inducing Complete and Durable Tumor Regression.JOURNAL OF MEDICINAL CHEMISTRY,61(15),6685-6704.
MLA	Qin, Chong,et al."Discovery of QCA570 as an Exceptionally Potent and Efficacious Proteolysis Targeting Chimera (PROTAC) Degrader of the Bromodomain and Extra-Terminal (BET) Proteins Capable of Inducing Complete and Durable Tumor Regression".JOURNAL OF MEDICINAL CHEMISTRY 61.15(2018):6685-6704.