Aminopyrazole based CDK9 PROTAC sensitizes pancreatic cancer cells to venetoclax

Bioorg Med Chem Lett. 2021 Jul 1:43:128061. doi: 10.1016/j.bmcl.2021.128061. Epub 2021 Apr 23.

Abstract

Cyclin-dependent kinase 9 (CDK9) is a member of the cyclin-dependent kinase (CDK) family which is involved in transcriptional regulation of several genes, including the oncogene Myc, and is a validated target for pancreatic cancer. Here we report the development of an aminopyrazole based proteolysis targeting chimera (PROTAC 2) that selectively degrades CDK9 (DC50 = 158 ± 6 nM). Mass spectrometry-based kinome profiling shows PROTAC 2 selectively degrades CDK9 in MiaPaCa2 cells and sensitizes them to Venetoclax mediated growth inhibition.

Keywords: Aminopyrazole; CDK; Cancer; PROTAC; Venetoclax.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Antineoplastic Agents / pharmacology
  • Bridged Bicyclo Compounds, Heterocyclic / pharmacology
  • Cell Proliferation / drug effects
  • Cyclin-Dependent Kinase 9 / antagonists & inhibitors*
  • Cyclin-Dependent Kinase 9 / metabolism
  • Dose-Response Relationship, Drug
  • Drug Screening Assays, Antitumor
  • Humans
  • Molecular Structure
  • Pancreatic Neoplasms / drug therapy*
  • Pancreatic Neoplasms / metabolism
  • Pancreatic Neoplasms / pathology
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Proteolysis / drug effects
  • Pyrazoles / chemistry
  • Pyrazoles / pharmacology*
  • Structure-Activity Relationship
  • Sulfonamides / pharmacology

Substances

  • Antineoplastic Agents
  • Bridged Bicyclo Compounds, Heterocyclic
  • Protein Kinase Inhibitors
  • Pyrazoles
  • Sulfonamides
  • CDK9 protein, human
  • Cyclin-Dependent Kinase 9
  • venetoclax