Discovery of High-Affinity Inhibitors of the BPTF Bromodomain

doi:10.1021/acs.jmedchem.1c00721

	Discovery of High-Affinity Inhibitors of the BPTF Bromodomain
	Lu, Tian 1,2,3; Lu, Haibo 4,5; Duan, Zhe 5; Wang, Jun 5; Han, Jie 5; Xiao, Senhao 5; Chen, HuanHuan 6; Jiang, Hao 5; Chen, Yu 5; Yang, Feng 5
刊名	JOURNAL OF MEDICINAL CHEMISTRY
	2021-08-26
卷号	64 期号:16 页码:12075-12088
ISSN号	0022-2623
DOI	10.1021/acs.jmedchem.1c00721
通讯作者	Lu, Wenchao(wclu@stanford.edu) ; Lin, Hua(hlin@fjnu.edu.cn) ; Luo, Cheng(cluo@simm.ac.cn)
英文摘要	The dysfunctional bromodomain PHD finger transcription factor (BPTF) exerts a pivotal influence in the occurrence and development of many human diseases, particularly cancers. Herein, through the structural decomposition of the reported BPTF inhibitor TP-238, the effective structural fragments were synthetically modified to obtain our lead compound DC-BPi-03. DC-BPi-03 was identified as a novel BPTF-BRD inhibitor with a moderate potency (IC50 = 698.3 +/- 21.0 nM). A structure-guided structure-activity relationship exploration gave rise to two BPTF inhibitors with much higher affinities, DC-BPi-07 and DC-BPi-11. Notably, DC-BPi-07 and DC-BPi-11 show selectivities 100-fold higher than those of other BRD targets. The cocrystal structures of BPTF in complex with DC-BPi-07 and DC-BPi-11 demonstrate the rationale of chemical efforts from the atomic level. Further study showed that DC-BPi-11 significantly inhibited leukemia cell proliferation.
资助项目	National Natural Science Foundation of China[81625022] ; National Natural Science Foundation of China[91853205] ; National Natural Science Foundation of China[81821005] ; National Natural Science Foundation of China[21820102008] ; Science and Technology Commission of Shanghai Municipality[18431907100] ; Science and Technology Commission of Shanghai Municipality[Y811298033] ; Science and Technology Commission of Shanghai Municipality[19XD1404700] ; scientific research innovation program Xiyuanjiang River Scholarship of the College of Life Sciences, Fujian Normal University ; State Key Laboratory of Drug Research[SIMM2105KF-07]
WOS关键词	PHD-FINGER ; PROTEIN
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	AMER CHEMICAL SOC
WOS记录号	WOS:000692012400017
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/297851]
专题	中国科学院上海药物研究所
通讯作者	Lu, Wenchao; Lin, Hua; Luo, Cheng
作者单位	1.Fujian Med Univ, Sch Pharm, Fuzhou, Peoples R China 2.Guizhou Univ Tradit Chinese Med, Guiyang 550025, Guizhou, Peoples R China 3.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210023, Peoples R China 4.Fudan Univ, Sch Pharm, Shanghai 201203, Peoples R China 5.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Drug Design & Discovery Ctr,Chem Biol Ctr, Shanghai 201203, Peoples R China 6.Chinese Acad Sci, Shanghai Inst Mat Med, Lab Pharmaceut Anal, Shanghai 201203, Peoples R China 7.Stanford Univ, Stanford Sch Med, Stanford Canc Inst, Stanford, CA 94305 USA 8.Fujian Normal Univ, Coll Life Sci, Biomed Res Ctr South China, Fuzhou 350117, Peoples R China
推荐引用方式 GB/T 7714	Lu, Tian,Lu, Haibo,Duan, Zhe,et al. Discovery of High-Affinity Inhibitors of the BPTF Bromodomain[J]. JOURNAL OF MEDICINAL CHEMISTRY,2021,64(16):12075-12088.
APA	Lu, Tian.,Lu, Haibo.,Duan, Zhe.,Wang, Jun.,Han, Jie.,...&Luo, Cheng.(2021).Discovery of High-Affinity Inhibitors of the BPTF Bromodomain.JOURNAL OF MEDICINAL CHEMISTRY,64(16),12075-12088.
MLA	Lu, Tian,et al."Discovery of High-Affinity Inhibitors of the BPTF Bromodomain".JOURNAL OF MEDICINAL CHEMISTRY 64.16(2021):12075-12088.