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

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.
Hao Shao 1,  David W Foley 1,  Shiliang Huang 1,  Abdullahi Y Abbas 1,  Frankie Lam 2,  Pavel Gershkovich 1,  Tracey D Bradshaw 1,  Chris Pepper 3,  Peter M Fischer 4,  Shudong Wang 5
Affiliations

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: peter.fischer@nottingham.ac.uk.
  • 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: shudong.wang@unisa.edu.au.
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.

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