Design, synthesis and anti-breast cancer evaluation of biaryl pyridine analogues as potent RSK inhibitors

Yi-Man Cui; Wei Li; Tian-Ze Shen; Yong-Xing Tao; Biao-Qi Liu; Xiao-Li Li; Rui-Han Zhang; De-Wei Jiang; Wei-Lie Xiao

doi:10.1016/j.bmcl.2022.128565

Design, synthesis and anti-breast cancer evaluation of biaryl pyridine analogues as potent RSK inhibitors

Bioorg Med Chem Lett. 2022 Mar 1:59:128565. doi: 10.1016/j.bmcl.2022.128565. Epub 2022 Jan 19.

Authors

Yi-Man Cui¹, Wei Li², Tian-Ze Shen¹, Yong-Xing Tao¹, Biao-Qi Liu¹, Xiao-Li Li¹, Rui-Han Zhang¹, De-Wei Jiang³, Wei-Lie Xiao⁴

Affiliations

¹ Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education and Yunnan Province, School of Chemical Science and Technology, Yunnan University, Kunming 650091, China.
² Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650223, China; Kunming College of Life Sciences, The University of the Chinese Academy of Sciences, Kunming 650201, China.
³ Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650223, China; Kunming College of Life Sciences, The University of the Chinese Academy of Sciences, Kunming 650201, China. Electronic address: jiangdewei@mail.kiz.ac.cn.
⁴ Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education and Yunnan Province, School of Chemical Science and Technology, Yunnan University, Kunming 650091, China. Electronic address: xiaoweilie@ynu.edu.cn.

PMID: 35065234
DOI: 10.1016/j.bmcl.2022.128565

Abstract

In order to discover and develop the new RSK kinase inhibitor, 50 pyridyl biaryl derivatives were designed and synthesized with LJH685 as the lead compound and their anti-tumor ability was tested. The results showed that the ability of 7d compound to inhibit the phosphorylation of YB-1 was comparable to that of LJH685. Among them, after preliminary screening, compound 7d showed good activity in inhibiting cell proliferation. Therefore, we took 7d as an example and performed molecular docking analysis on it. Judging from the overlapping combination diagram with LJH685, the results have verified that compound 7d has a similar skeleton to LJH685 and has a similar docking effect with RSK. Therefore, compound 7d is in line with the RSK inhibitor we designed and could be developed to a promising anti-tumor drug in the future.

Keywords: Breast Cancer; LJH685; RSK inhibitor; Structure-activity relationship; YB-1 phosphorylation.

Publication types

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

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Drug Design*
Drug Screening Assays, Antitumor
Humans
Molecular Docking Simulation
Molecular Structure
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Pyridines / chemical synthesis
Pyridines / chemistry
Pyridines / pharmacology*
Ribosomal Protein S6 Kinases, 90-kDa / antagonists & inhibitors*
Ribosomal Protein S6 Kinases, 90-kDa / metabolism
Structure-Activity Relationship
Tumor Cells, Cultured

Substances

Antineoplastic Agents
Protein Kinase Inhibitors
Pyridines
Ribosomal Protein S6 Kinases, 90-kDa