Development of Dimethylisoxazole-Attached Imidazo[1,2-]pyridines As Potent and Selective CBP/P300 Inhibitors

Overview

Journal J Med Chem

Publisher American Chemical Society

Specialty Chemistry

Date 2021 Apr 19

PMID 33872011

Citations 6

Authors

Alex Muthengi

Virangika K Wimalasena

Hailemichael O Yosief

Melissa J Bikowitz

Logan H Sigua

Tingjian Wang

Deyao Li

Zied Gaieb

Gagan Dhawan

Shuai Liu

Jon Erickson

Rommie E Amaro

Ernst Schonbrunn

Jun Qi

Wei Zhang

Affiliations

Soon will be listed here.

Abstract

The use of epigenetic bromodomain inhibitors as anticancer therapeutics has transitioned from targeting bromodomain extraterminal domain (BET) proteins into targeting non-BET bromodomains. The two most relevant non-BET bromodomain oncology targets are cyclic AMP response element-binding protein (CBP) and E1A binding protein P300 (EP300). To explore the growing CBP/EP300 interest, we developed a highly efficient two-step synthetic route for dimethylisoxazole-attached imidazo[1,2-]pyridine scaffold-containing inhibitors. Our efficient two-step reactions enabled high-throughput synthesis of compounds designed by molecular modeling, which together with structure-activity relationship (SAR) studies facilitated an overarching understanding of selective targeting of CBP/EP300 over non-BET bromodomains. This led to the identification of a new potent and selective CBP/EP300 bromodomain inhibitor, UMB298 (compound , CBP IC 72 nM and bromodomain 4, BRD4 IC 5193 nM). The SAR we established is in good agreement with literature-reported CBP inhibitors, such as CBP30, and demonstrates the advantage of utilizing our two-step approach for inhibitor development of other bromodomains.

Citing Articles

Dysregulation of the p300/CBP histone acetyltransferases in human cancer.

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Discovery of an EP300 Inhibitor using Structure-based Virtual Screening and Bioactivity Evaluation.

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Group 3 medulloblastoma transcriptional networks collapse under domain specific EP300/CBP inhibition.

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