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

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

doi:10.1016/j.ejmech.2021.113391

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. Epub 2021 Mar 26.

Authors

Mingfeng Yu¹, Yi Long¹, Yuchao Yang¹, Manjun Li¹, Theodosia Teo¹, Benjamin Noll¹, Stephen Philip¹, Shudong Wang²

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.

MeSH terms

Administration, Oral
Animals
Antineoplastic Agents / administration & dosage
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Apoptosis / drug effects
Biological Availability
Cell Line, Tumor
Cell Proliferation / drug effects
Cyclin-Dependent Kinase 8 / antagonists & inhibitors*
Cyclin-Dependent Kinase 8 / metabolism
Dose-Response Relationship, Drug
Drug Discovery*
Drug Screening Assays, Antitumor
Humans
Male
Mice
Mice, Inbred BALB C
Molecular Structure
Protein Kinase Inhibitors / administration & dosage
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Rats
Rats, Sprague-Dawley
Structure-Activity Relationship

Substances

Antineoplastic Agents
Protein Kinase Inhibitors
CDK8 protein, human
Cyclin-Dependent Kinase 8