Open AccessDiscovery of a Potent and Selective Covalent p300/CBP Inhibitor
Author(s) -
Anthony Mastracchio,
Chunqiu Lai,
Enrico L. DiGiammarino,
Damien Ready,
Loren Lasko,
Kenneth D. Bromberg,
William J. McClellan,
Debra Montgomery,
Vlasios Manaves,
Bailin Shaw,
Mikkel A. Algire,
Melanie J. Patterson,
Chaohong Sun,
Saul H. Rosenberg,
Albert Lai,
Michel Michaelides
Publication year - 2021
Publication title -
acs medicinal chemistry letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 66
ISSN - 1948-5875
DOI - 10.1021/acsmedchemlett.0c00654
Subject(s) - creb binding protein , covalent bond , chemistry , histone acetyltransferases , cysteine , small molecule , non covalent interactions , p300 cbp transcription factors , computational biology , biochemistry , histone , biology , gene , enzyme , transcription factor , creb , molecule , hydrogen bond , organic chemistry
Aberrant gene activation driven by the histone acetyltransferases p300 and CREB binding protein (CBP) has been linked to several diseases, including cancers. Because of this, many efforts have been aimed toward the targeting of the closely related paralogues, p300 and CBP, but these endeavors have been exclusively directed toward noncovalent inhibitors. X-ray crystallography of A-485 revealed that both p300 and CBP possess a cysteine (C1450) near the active site, thus rendering covalent inhibition an attractive chemical approach. Herein we report the development of compound 2 , an acrylamide-based inhibitor of p300/CBP that forms a covalent adduct with C1450. We demonstrated using mass spectrometry that compound 2 selectively targets C1450, and we also validated covalent binding using kinetics experiments and cellular washout studies. The discovery of covalent inhibitor 2 gives us a unique tool for the study of p300/CBP biology.