Structure-based design of highly selective 2,4,5-trisubstituted pyrimidine CDK9 inhibitors as anti-cancer agents

Hao Shao; David W Foley; Shiliang Huang; Abdullahi Y Abbas; Frankie Lam; Pavel Gershkovich; Tracey D Bradshaw; Chris Pepper; Peter M Fischer; Shudong Wang

doi:10.1016/j.ejmech.2021.113244

Structure-based design of highly selective 2,4,5-trisubstituted pyrimidine CDK9 inhibitors as anti-cancer agents

Eur J Med Chem. 2021 Mar 15:214:113244. doi: 10.1016/j.ejmech.2021.113244. Epub 2021 Feb 2.

Authors

Affiliations

¹ School of Pharmacy and Biodiscovery Institute, University of Nottingham, University Park, Nottingham, NG7 2RD, UK.
² Drug Discovery and Development, Clinical and Health Sciences, University of South Australia, Adelaide, SA, 5001, Australia.
³ Brighton and Sussex Medical School, University of Sussex, Brighton, East Sussex, BN1 9PX, UK.
⁴ School of Pharmacy and Biodiscovery Institute, University of Nottingham, University Park, Nottingham, NG7 2RD, UK. Electronic address: [email protected].
⁵ School of Pharmacy and Biodiscovery Institute, University of Nottingham, University Park, Nottingham, NG7 2RD, UK; Drug Discovery and Development, Clinical and Health Sciences, University of South Australia, Adelaide, SA, 5001, Australia. Electronic address: [email protected].

PMID: 33581551
DOI: 10.1016/j.ejmech.2021.113244

Abstract

Cyclin-dependent kinases (CDKs) are a family of Ser/Thr kinases involved in cell cycle and transcriptional regulation. CDK9 regulates transcriptional elongation and this unique property has made it a potential target for several diseases. Due to the conserved ATP binding site, designing selective CDK9 inhibitors has been challenging. Here we report our continued efforts in the optimization of 2,4,5-tri-substituted pyrimidine compounds as potent and selective CDK9 inhibitors. The most selective compound 30m was >100-fold selective for CDK9 over CDK1 and CDK2. These compounds showed broad anti-proliferative activities in various solid tumour cell lines and patient-derived chronic lymphocytic leukaemia (CLL) cells. Decreased phosphorylation of the carboxyl terminal domain (CTD) of RNAPII at Ser-2 and down-regulation of anti-apoptotic protein Mcl-1 were confirmed in both the ovarian cancer model A2780 and patient-derived CLL cells.

Keywords: Anti-Cancer agents; Apoptosis; CDK9 inhibitor; Chronic lymphocytic leukaemia; Mcl-1; RNA polymerase II.

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Apoptosis / drug effects
Cell Proliferation / drug effects
Cells, Cultured
Cyclin-Dependent Kinase 9 / antagonists & inhibitors*
Cyclin-Dependent Kinase 9 / metabolism
Dose-Response Relationship, Drug
Drug Design*
Drug Screening Assays, Antitumor
Humans
Models, Molecular
Molecular Structure
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Pyrimidines / chemical synthesis
Pyrimidines / chemistry
Pyrimidines / pharmacology*
Structure-Activity Relationship

Substances

Antineoplastic Agents
Protein Kinase Inhibitors
Pyrimidines
CDK9 protein, human
Cyclin-Dependent Kinase 9
pyrimidine