Xinrong Tian; Dominic Suarez; Douglas Thomson; William Li; Elizabeth A. King; Louis LaFrance; Jeffrey Boehm; Linda Barton; Christina Di Marco; Cuthbert Martyr; Reema Thalji; Jesus Medina; Steven Knight; Dirk Heerding; Enoch Gao; Eldridge Nartey; Ted Cecconie; Christopher Nixon; Guofeng Zhang; Thomas J. Berrodin; Christopher Phelps; Amish Patel; Xiaopeng Bai; Ken Lind; Ninad Prabhu; Jeffrey Messer; Zhengrong Zhu; Lisa Shewchuk; Rob Reid; Alan P. Graves; Charles McHugh; Biju Mangatt
J. Med. Chem., 2022, 65(21), 14391–14408
https://doi.org/10.1021/acs.jmedchem.2c00670

Abstract

E1A binding protein (p300) and CREB binding protein (CBP) are two highly homologous and multidomain histone acetyltransferases. These two proteins are involved in many cellular processes by acting as coactivators of a large number of transcription factors. Dysregulation of p300/CBP has been found in a variety of cancers and other diseases, and inhibition has been shown to decrease Myc expression. Herein, we report the identification of a series of highly potent, proline-based small-molecule p300/CBP histone acetyltransferase (HAT) inhibitors using DNA-encoded library technology in combination with high-throughput screening. The strategy of reducing ChromlogD and fluorination of metabolic soft spots was explored to improve the pharmacokinetic properties of potent p300 inhibitors. Fluorination of both cyclobutyl and proline rings of 22 led to not only reduced clearance but also improved cMyc cellular potency.