European Journal of Medicinal Chemistry p. 238 - 252 (2018)
Update date:2022-08-15
Topics:
Xiang, Qiuping
Wang, Chao
Zhang, Yan
Xue, Xiaoqian
Song, Ming
Zhang, Cheng
Li, Chenchang
Wu, Chun
Li, Kuai
Hui, Xiaoyan
Zhou, Yulai
Smaill, Jeff B.
Patterson, Adam V.
Wu, Donghai
Ding, Ke
Xu, Yong
The CREB (cAMP responsive element binding protein) binding protein (CBP) and its homolog EP300 have emerged as new therapeutic targets for the treatment of cancer and inflammatory diseases. Here we report the identification, optimization and evaluation of 1-(1H-indol-1-yl)ethanone derivatives as CBP/EP300 inhibitors starting from fragment-based virtual screening (FBVS). A cocrystal structure of the inhibitor (22e) in complex with CBP provides a solid structural basis for further optimization. The most potent compound 32h binds to the CBP bromodomain and has an IC50 value of 0.037 μM in the AlphaScreen assay which was 2 times more potent than the reported CBP bromodomain inhibitor SGC-CBP30 in our hands. 32h also exhibit high selectivity for CBP/EP300 over other bromodomain-containing proteins. Notably, the ester derivative (29h) of compound 32h markedly inhibits cell growth in several prostate cancer cell lines including LNCaP, 22Rv1 and LNCaP derived C4-2B. Compound 29h suppresses the mRNA expression of full length AR (AR-FL), AR target genes and other oncogene in LNCaP cells. 29h also reduces the expression of PSA, the biomarker of prostate cancer. CBP/EP300 inhibitor 29h represents a promising lead compound for the development of new therapeutics for the treatment of castration-resistant prostate cancer.
View MoreBaoding City Light Industry And Textiles Imp.& Exp. Corp. Chemical Department.
Contact:86-312-3262436
Address:NO.658 CHAOYANG SOUTH STREET,BAODING CITY HEBEI CHINA
Purestar Chem Enterprise Co.,Ltd
website:http://www.purestarchem.com
Contact:05722157374
Address:no235.huanchengdong Rd
Xi'an Tizan Tech & Industry Co., Ltd.
Contact:86-18629066522
Address:C3009 TANG FENG INTERNATIONAL PLAZA, NO.18 FENGHUI NAN ROAD, XI'AN HIGH TECH ZONE, 710075 CHINA.
Taixing Shenfeng Chemical Co., Ltd.
Contact:+86-523-87117033, 87117666
Address:4# Yinsanlu, Huangqiao town, Taixing, Jiangsu, China.
ANHUI CHEM-BRIGHT BIOENGINEERING CO.,LTD
Contact:86-561-4080321
Address:No.8 Lieshan Industrial Zone of Huaibei
Doi:10.1248/cpb.30.874
(1982)Doi:10.1016/j.bmcl.2009.03.120
(2009)Doi:10.3987/COM-09-S(S)123
(2010)Doi:10.1021/ja101851v
(2010)Doi:10.1016/S0040-4039(00)95242-0
(1989)Doi:10.1002/hlca.19770600528
(1977)