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

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

doi:10.1016/j.bioorg.2022.105768

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

Bioorg Chem. 2022 Jun:123:105768. doi: 10.1016/j.bioorg.2022.105768. Epub 2022 Mar 26.

Authors

Haibo Lu¹, Tian Lu², Shijia Zu³, Zhe Duan⁴, Yiman Guang³, Qi Li⁵, Jingyi Ma⁶, Dongying Chen⁶, Bo Li⁵, Wenchao Lu⁷, Hualiang Jiang⁵, Cheng Luo⁸, Deyong Ye⁹, Kaixian Chen¹⁰, Hua Lin¹¹

Affiliations

¹ School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, China; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
² State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China; GuiZhou University of Traditional Chinese Medicine, Guizhou 550025, China.
³ State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China; University of Chinese Academy of Sciences, 19 Yuquan Road, Beijing 100049, China.
⁴ State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China; School of Pharmacy, Nanchang University, Nanchang 330006, China.
⁵ State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
⁶ Laboratory of Pharmaceutical Analysis, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Zhangjiang Hi-Tech Park, Shanghai, 201203, China; University of Chinese Academy of Sciences, 19 Yuquan Road, Beijing 100049, China.
⁷ Stanford Cancer Institute, Stanford School of Medicine, Stanford University, Stanford, CA, 94305, USA.
⁸ School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, China; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China; University of Chinese Academy of Sciences, 19 Yuquan Road, Beijing 100049, China.
⁹ School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, China. Electronic address: dyye@shmu.edu.cn.
¹⁰ School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, China; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China; University of Chinese Academy of Sciences, 19 Yuquan Road, Beijing 100049, China. Electronic address: kxchen@simm.ac.cn.
¹¹ Biomedical Research Center of South China, College of Life Sciences, Fujian Normal University, Fuzhou 350117, China; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China. Electronic address: hlin@fjnu.edu.cn.

PMID: 35378372
DOI: 10.1016/j.bioorg.2022.105768

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.

Keywords: BPTF bromodomain; CECR2 bromodomain; Chemical probe; SAR study; Small-molecule inhibitor.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Molecular Docking Simulation
Protein Domains
Pyrimidines* / pharmacology
Structure-Activity Relationship
Transcription Factors* / chemistry

Substances

Pyrimidines
Transcription Factors