Design, synthesis and biological evaluation of 2-aminopyridine derivatives as USP7 inhibitors

Xiaoming Xu; Mingchen Wang; Hailong Xu; Na Liu; Kaixian Chen; Cheng Luo; Shijie Chen; Hua Chen

doi:10.1016/j.bioorg.2022.106128

Design, synthesis and biological evaluation of 2-aminopyridine derivatives as USP7 inhibitors

Bioorg Chem. 2022 Dec:129:106128. doi: 10.1016/j.bioorg.2022.106128. Epub 2022 Sep 10.

Authors

Xiaoming Xu¹, Mingchen Wang², Hailong Xu¹, Na Liu¹, Kaixian Chen², Cheng Luo³, Shijie Chen⁴, Hua Chen⁵

Affiliations

¹ Key Laboratory of Chemical Biology of Hebei Province, College of Chemistry and Environmental Science, Hebei University, Baoding 071002, China.
² The Center for Chemical Biology, Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; School of Life Science and Technology, Shanghai Tech University, Shanghai 200031, China; University of Chinese Academy of Sciences, Beijing 100049, China.
³ The Center for Chemical Biology, Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; School of Life Science and Technology, Shanghai Tech University, Shanghai 200031, China; University of Chinese Academy of Sciences, Beijing 100049, China; School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China.
⁴ The Center for Chemical Biology, Drug Discovery and Design Center, 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. Electronic address: shijiechen@simm.ac.cn.
⁵ Key Laboratory of Chemical Biology of Hebei Province, College of Chemistry and Environmental Science, Hebei University, Baoding 071002, China. Electronic address: hua-todd@163.com.

PMID: 36113266
DOI: 10.1016/j.bioorg.2022.106128

Abstract

A series of novel 2-aminopyridine derivatives 1-26 have been designed and synthesized by structural modifications on a lead USP7 inhibitor, GNE6640. All the compounds were evaluated for their USP7 inhibitory activities. The results showed that most of the compounds have good USP7 inhibitory activities at the concentration of 50 μM. Among them, compounds 7, 14 and 21 are the most potential ones from each category with the IC₅₀ values of 7.6 ± 0.1 μM, 17.0 ± 0.2 μM and 11.6 ± 0.5 μM, respectively. Compounds 7 and 21 expressed significant binding interactions with USP7 by surface plasmon resonance (SPR)-based binding assay, but both of them presented moderate antiproliferative activities against HCT116 cells. They could effectively promote MDM2 degradation, p53 stabilization and p21 gene expression in the western blot analysis.

Keywords: Aminopyridine; Colorectal carcinoma; MDM2; P53 and p21; Suzuki coupling reaction; USP7 inhibitors.

Publication types

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

MeSH terms

Aminopyridines* / pharmacology
Antineoplastic Agents* / chemistry
Cell Line, Tumor
Cell Proliferation
HCT116 Cells
Humans
Tumor Suppressor Protein p53 / metabolism
Ubiquitin-Specific Peptidase 7 / metabolism

Substances

Ubiquitin-Specific Peptidase 7
alpha-aminopyridine
Aminopyridines
Tumor Suppressor Protein p53
Antineoplastic Agents
USP7 protein, human