Discovery of a potent, highly selective, and orally bioavailable inhibitor of CDK8 through a structure-based optimisation

Eur J Med Chem. 2021 Jun 5:218:113391. doi: 10.1016/j.ejmech.2021.113391.

Mingfeng Yu ¹, Yi Long ¹, Yuchao Yang ¹, Manjun Li ¹, Theodosia Teo ¹, Benjamin Noll ¹, Stephen Philip ¹, Shudong Wang ²

Affiliations

1 Drug Discovery and Development, Cancer Research Institute, Clinical and Health Sciences, University of South Australia, Adelaide, South Australia, 5000, Australia.
2 Drug Discovery and Development, Cancer Research Institute, Clinical and Health Sciences, University of South Australia, Adelaide, South Australia, 5000, Australia. Electronic address: shudong.wang@unisa.edu.au.

PMID: 33823391 DOI: 10.1016/j.ejmech.2021.113391

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.

Keywords

Anti-proliferation mechanism; CDK8 inhibitor; Kinase selectivity; MV4-11; Oral bioavailability; Structure-based optimisation.

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