Targeting cyclin-dependent kinases: From pocket specificity to drug selectivity.

Autor: Huang Y; School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, 110016, People's Republic of China., Liu W; School of Pharmaceutical Sciences, Tsinghua University, Haidian Dist., Beijing, 100084, People's Republic of China., Zhao C; Department of Pharmacy, General Hospital of Northern Theater Command, Shenyang, 110840, People's Republic of China., Shi X; School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, 110016, People's Republic of China., Zhao Q; School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, 110016, People's Republic of China; Department of Pharmacy, General Hospital of Northern Theater Command, Shenyang, 110840, People's Republic of China. Electronic address: zhaoqingchun1967@163.com., Jia J; School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, 110016, People's Republic of China. Electronic address: jiajingming@163.com., Wang A; School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, 110016, People's Republic of China. Electronic address: sywanganhua@163.com.
Jazyk: angličtina
Zdroj: European journal of medicinal chemistry [Eur J Med Chem] 2024 Sep 05; Vol. 275, pp. 116547. Date of Electronic Publication: 2024 May 29.
DOI: 10.1016/j.ejmech.2024.116547
Abstrakt: The development of selective modulators of cyclin-dependent kinases (CDKs), a kinase family with numerous members and functional variations, is a significant preclinical challenge. Recent advancements in crystallography have revealed subtle differences in the highly conserved CDK pockets. Exploiting these differences has proven to be an effective strategy for achieving excellent drug selectivity. While previous reports briefly discussed the structural features that lead to selectivity in individual CDK members, attaining inhibitor selectivity requires consideration of not only the specific structures of the target CDK but also the features of off-target members. In this review, we summarize the structure-activity relationships (SARs) that influence selectivity in CDK drug development and analyze the pocket features that lead to selectivity using molecular-protein binding models. In addition, in recent years, novel CDK modulators have been developed, providing more avenues for achieving selectivity. These cases were also included. We hope that these efforts will assist in the development of novel CDK drugs.
Competing Interests: Declaration of competing interest Dear Editor, All authors have approved this manuscript. No author has financial or other contractual agreements that might cause conflicts of interest.
(Copyright © 2024 Elsevier Masson SAS. All rights reserved.)
Databáze: MEDLINE
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