Journal of Medicinal Chemistry p. 8202 - 8211 (2018)
Update date:2022-08-03
Topics:
Kharenko, Olesya A.
Patel, Reena G.
Brown, S. David
Calosing, Cyrus
White, Andre
Lakshminarasimhan, Damodharan
Suto, Robert K.
Duffy, Bryan C.
Kitchen, Douglas B.
McLure, Kevin G.
Hansen, Henrik C.
Van Der Horst, Edward H.
Young, Peter R.
BET proteins are key epigenetic regulators that regulate transcription through binding to acetylated lysine (AcLys) residues of histones and transcription factors through bromodomains (BDs). The disruption of this interaction with small molecule bromodomain inhibitors is a promising approach to treat various diseases including cancer, autoimmune and cardiovascular diseases. Covalent inhibitors can potentially offer a more durable target inhibition leading to improved in vivo pharmacology. Here we describe the design of covalent inhibitors of BRD4(BD1) that target a methionine in the binding pocket by attaching an epoxide warhead to a suitably oriented noncovalent inhibitor. Using thermal denaturation, MALDI-TOF mass spectrometry, and an X-ray crystal structure, we demonstrate that these inhibitors selectively form a covalent bond with Met149 in BRD4(BD1) but not other bromodomains and provide durable transcriptional and antiproliferative activity in cell based assays. Covalent targeting of methionine offers a novel approach to drug discovery for BET proteins and other targets.
View Morewebsite:http://www.sigmaaldrich.com
Contact:800 558-9160
Address:Industriestrasse 25CH-9471 Buchs SGSwitzerland
HAINAN JINYING IMPORT AND EXPORT CO. LTD
Contact:+86-898-32875423
Address:A SECTION 19TH FL, TIMES SQUARE, NO.2 GUO MAO AVENUE HAIKOU, HAINAN, P. R. OF CHINA
Changzhou Jiana Chemical Co.,Ltd
website:http://www.jianachem.com
Contact:86-0519-88731808
Address:Zhenglu Town Wujin City, Jiangsu Province
Shanghai Yurui Biotechnology(Anyang) Pharmaceutical Co., Ltd
Contact:+86-0372-3662335 +86-0372-3661988
Address:hanling industrial park anyang
Yangzhou Siyu Chemical Co.,Ltd.
Contact:+86-514-87325867 13358126196
Address:Room 620 Exposition Pavilion,No. 98 Huaihai Road,Guangling District,Yangzhou City, Jiangsu Province
Doi:10.1002/cmdc.201400049
(2014)Doi:10.1016/j.tetasy.2006.06.031
(2006)Doi:10.1016/0022-328X(94)05192-E
(1995)Doi:10.1038/s41557-020-0455-y
(2020)Doi:10.1021/ja953529i
(1996)Doi:10.1002/ejic.201402099
(2014)