Discovery of a Potent and Selective Covalent p300/CBP Inhibitor

• Published in: ACS medicinal chemistry letters Vol. 12; no. 5; pp. 726 - 731
• Main Authors: Mastracchio, Anthony, Lai, Chunqiu, Digiammarino, Enrico, Ready, Damien B, Lasko, Loren M, Bromberg, Kenneth D, McClellan, William J, Montgomery, Debra, Manaves, Vlasios, Shaw, Bailin, Algire, Mikkel, Patterson, Melanie J, Sun, Chaohong C, Rosenberg, Saul, Lai, Albert, Michaelides, Michael R
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 13.05.2021; Amer Chemical Soc
• Subjects: Chemistry, Medicinal; Letter; Life Sciences & Biomedicine; Pharmacology & Pharmacy; Science & Technology; p300; CBP; prostate cancer; histone acetyltransferase; covalent inhibitor; H3K27Ac; SERINE
• ISSN: 1948-5875; 1948-5875
• DOI: 10.1021/acsmedchemlett.0c00654

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.