posted on 2021-04-05, 16:38authored byAnthony Mastracchio, Chunqiu Lai, Enrico Digiammarino, Damien B. Ready, Loren M. Lasko, Kenneth D. Bromberg, William J. McClellan, Debra Montgomery, Vlasios Manaves, Bailin Shaw, Mikkel Algire, Melanie J. Patterson, Chaohong C. Sun, Saul Rosenberg, Albert Lai, Michael R. Michaelides
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.