Discovery of a potent, highly selective, and orally bioavailable inhibitor of CDK8 through a structure-based optimisation
Files
(Published version)
Date
2021
Authors
Yu, M.
Long, Y.
Yang, Y.
Li, M.
Teo, T.
Noll, B.
Philip, S.
Wang, S.
Editors
Advisors
Journal Title
Journal ISSN
Volume Title
Type:
Journal article
Citation
European Journal of Medicinal Chemistry, 2021; 218(113391)
Statement of Responsibility
Conference Name
Abstract
CDK8 is deregulated in multiple types of human cancer and is viewed as a therapeutic target for the treatment of the disease. Accordingly, the search for small-molecule inhibitors of CDK8 is being intensified. Capitalising on our initial discovery of AU1-100, a potent CDK8 inhibitor yet with a limited degree of kinase selectivity, a structure-based optimisation was carried out, with a series of new multi-substituted pyridines rationally designed, chemically prepared and biologically evaluated. Such endeavour has culminated in the identification of 42, a more potent CDK8 inhibitor with superior kinomic selectivity and oral bioavailability. The mechanism underlying the anti-proliferative effect of 42 on MV4-11 cells was studied, revealing that the compound arrested the G1 cell cycle and triggered apoptosis. The low risk of hepato- and cardio-toxicity of 42 was estimated. These findings merit further investigation of 42 as a targeted cancer therapeutic.
School/Discipline
Dissertation Note
Provenance
Description
Data source: Supplementary data, https://doi.org/10.1016/j.ejmech.2021.113391
Access Status
Rights
Copyright 2021 Elsevier Masson
Access Condition Notes: Accepted manuscript available 1 April 2023