Potent and orally bioavailable CDK8 inhibitors: Design, synthesis, structure-activity relationship analysis and biological evaluation

Mingfeng Yu; Theodosia Teo; Yuchao Yang; Manjun Li; Yi Long; Stephen Philip; Benjamin Noll; Gary K Heinemann; Sarah Diab; Preethi Eldi; Laychiluh Mekonnen; Abel T Anshabo; Muhammed H Rahaman; Robert Milne; John D Hayball; Shudong Wang

doi:10.1016/j.ejmech.2021.113248

Potent and orally bioavailable CDK8 inhibitors: Design, synthesis, structure-activity relationship analysis and biological evaluation

Eur J Med Chem. 2021 Mar 15:214:113248. doi: 10.1016/j.ejmech.2021.113248. Epub 2021 Feb 3.

Authors

Affiliations

¹ Drug Discovery and Development, Cancer Research Institute, Clinical and Health Sciences, University of South Australia, Adelaide, South Australia, 5000, Australia.
² Experimental Therapeutics, Cancer Research Institute, Clinical and Health Sciences, University of South Australia, Adelaide, South Australia, 5000, Australia.
³ 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: 33571827
DOI: 10.1016/j.ejmech.2021.113248

Abstract

CDK8 regulates transcription either by phosphorylation of transcription factors or, as part of a four-subunit kinase module, through a reversible association of the kinase module with the Mediator complex, a highly conserved transcriptional coactivator. Deregulation of CDK8 has been found in various types of human cancer, while the role of CDK8 in supressing anti-cancer response of natural killer cells is being understood. Currently, CDK8-targeting cancer drugs are highly sought-after. Herein we detail the discovery of a series of novel pyridine-derived CDK8 inhibitors. Medicinal chemistry optimisation gave rise to 38 (AU1-100), a potent CDK8 inhibitor with oral bioavailability. The compound inhibited the proliferation of MV4-11 acute myeloid leukaemia cells with the kinase activity of cellular CDK8 dampened. No systemic toxicology was observed in the mice treated with 38. These results warrant further pre-clinical studies of 38 as an anti-cancer agent.

Keywords: CDK8 inhibitor; Drug-like properties; Pharmacokinetics; Structure-activity relationship; Toxicity.

MeSH terms

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

Substances

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