Design, synthesis and biological evaluation of (R)-5-methylpyrrolidin-2-ones as p300 bromodomain inhibitors with Anti-Tumor activities in multiple tumor lines

Ruiqi Liu; Hong Yang; Zonglong Chen; Kaixin Zhou; Qiongyu Shi; Jiayi Li; Yuting Huang; Xun Huang; Yingxia Li

doi:10.1016/j.bioorg.2022.105803

Design, synthesis and biological evaluation of (R)-5-methylpyrrolidin-2-ones as p300 bromodomain inhibitors with Anti-Tumor activities in multiple tumor lines

Bioorg Chem. 2022 Jul:124:105803. doi: 10.1016/j.bioorg.2022.105803. Epub 2022 Apr 12.

Authors

Ruiqi Liu¹, Hong Yang², Zonglong Chen³, Kaixin Zhou⁴, Qiongyu Shi², Jiayi Li⁵, Yuting Huang⁶, Xun Huang⁷, Yingxia Li⁸

Affiliations

¹ Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai 201203, China; School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China.
² Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
³ Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai 201203, China.
⁴ Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China; School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China.
⁵ School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, UCAS, Hangzhou 310024, China; University of Chinese Academy of Sciences, Beijing 100049, China.
⁶ Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China.
⁷ Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, UCAS, Hangzhou 310024, China; University of Chinese Academy of Sciences, Beijing 100049, China. Electronic address: xhuang@simm.ac.cn.
⁸ Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai 201203, China. Electronic address: liyx417@fudan.edu.cn.

PMID: 35439627
DOI: 10.1016/j.bioorg.2022.105803

Abstract

p300/CBP bromodomain plays an important role in transcriptional regulation, and its overexpression is closely related to various diseases such as cancers. Two inhibitors of this target are currently in clinical trials but only CCS1477 (A1) have been published with the chemical structure. Herein, we modified the structure of CCS1477 based on the principle of bioisosterism and reasonable scaffold hopping, and discovered a series of new p300 bromodomain inhibitors with improved potency. More tumor cell lines sensitive to p300/CBP bromodomain inhibition were also identified. Among our new inhibitors, (R)-5-methylpyrrolidin-2-one derivitive B4 was the most potent one which showed comparable inhibitory activity against p300 (IC₅₀ = 0.060 μM) as lead A1 (IC₅₀ = 0.064 μM) at molecular level, and performed more potent proliferation inhibitory activities on various tumor cells than A1. Further we found that compound B4 had the high cell permeability and overcame the defect of the high efflux rate of A1, which could also explain the possible reason why B4 showed more potent inhibitory activities on sensitive tumor cells than lead A1. Western blotting analysis proved the target effects that B4 could suppress the expression of c-Myc and reduce H3K27 acetylation significantly. Liver microsomal metabolic stability assay and hERG channel inhibition evaluation illustrate compound B4 is metabolic stabilizable in human liver microsomes and has no hERG risk, which further demonstrate the good drug-likeness of B4. Therefore, compound B4 is a promising compound for further optimization and development.

Keywords: Bromodomain inhibitors; CCS1477; Epigenetics; p300/CBP.

Publication types

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

MeSH terms

Cell Line, Tumor
Enzyme Inhibitors / pharmacology
Humans
Nuclear Proteins*
Protein Domains
Transcription Factors*

Substances

Enzyme Inhibitors
Nuclear Proteins
Transcription Factors