Discovery of a highly potent CECR2 bromodomain inhibitor with 7H-pyrrolo[2,3-d] pyrimidine scaffold.

Abstract

Cat eye syndrome chromosome region candidate 2 (CECR2) bromodomain is a module of CECR2-containing remodeling factor (CERF), which is a chromatin remodeling complex correlating with transcriptional control and adjustment of chromatin architecture. Potent chemical probes would be beneficial to gain insights into the biochemical and pharmacological functions of CECR2 BRD. Herein, we report the discovery of a series of CECR2 BRD inhibitors with 7H-pyrrolo[2,3-d] pyrimidine scaffold based on molecular docking model of TP-248 and CECR2 BRD. The most potent inhibitor of this series, DC-CBi-22 with IC50 of 8.0 ± 1.4 nM against CECR2 BRD and selectivity over BPTF BRD up to 24.9-fold. The SARs were detailed according to molecular docking. DC-CBi-22 would serve as a useful chemical probe for the study of CECR2.

• Authors: Haibo Lu, Tian Lu, Shijia Zu, Zhe Duan, Yiman Guang, Qi Li, Jingyi Ma, Dongying Chen, Bo Li, Wenchao Lu, Hualiang Jiang, Cheng Luo, Deyong Ye, Kaixian Chen, Hua Lin
• Journal: Bioorganic chemistry (Bioorg Chem) Vol. 123 Pg. 105768 (06 2022) ISSN: 1090-2120 [Electronic] United States
• PMID: 35378372 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2022 Elsevier Inc. All rights reserved.

Chemical References

• Pyrimidines
• Transcription Factors

Topics

• Molecular Docking Simulation
• Protein Domains
• Pyrimidines (pharmacology)
• Structure-Activity Relationship
• Transcription Factors (chemistry)