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Aminopyrazole based CDK9 PROTAC sensitizes pancreatic cancer cells to venetoclax

Hannah M King1, Sandeep Rana1, Sydney P Kubica1

  • 1Eppley Institute for Cancer Research, University of Nebraska Medical Center, Omaha, NE 68022, USA.

Bioorganic & Medicinal Chemistry Letters
|April 25, 2021
PubMed

Insights

A novel proteolysis targeting chimera (PROTAC) selectively degrades cyclin-dependent kinase 9 (CDK9), a key target in pancreatic cancer. This compound shows promise in cancer therapy by sensitizing cells to existing treatments.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • Cyclin-dependent kinase 9 (CDK9) is crucial for transcriptional regulation and is implicated in oncogenesis, particularly in pancreatic cancer.
  • CDK9 is a validated therapeutic target for pancreatic ductal adenocarcinoma.
  • Targeting CDK9 offers a potential strategy for novel pancreatic cancer treatments.

Purpose of the Study:

  • To develop and characterize a novel proteolysis targeting chimera (PROTAC) for selective CDK9 degradation.
  • To evaluate the efficacy of the PROTAC in degrading CDK9 in pancreatic cancer cells.
  • To assess the potential of the PROTAC in combination therapy for pancreatic cancer.

Main Methods:

  • Development of an aminopyrazole-based PROTAC molecule (PROTAC 2).
  • Assessment of CDK9 degradation using DC50 values.
  • Kinome profiling via mass spectrometry in MiaPaCa2 cells.
  • Evaluation of cell sensitization to Venetoclax.

Main Results:

  • PROTAC 2 selectively degrades CDK9 with a DC50 of 158 ± 6 nM.
  • Mass spectrometry confirmed selective CDK9 degradation in MiaPaCa2 pancreatic cancer cells.
  • PROTAC 2 sensitized MiaPaCa2 cells to Venetoclax-mediated growth inhibition.

Conclusions:

  • The developed PROTAC molecule effectively and selectively degrades CDK9.
  • This PROTAC demonstrates potential as a therapeutic agent for pancreatic cancer, enhancing sensitivity to Venetoclax.
  • Targeted CDK9 degradation represents a promising strategy for pancreatic cancer treatment.
Keywords:
AminopyrazoleCDKCancerPROTACVenetoclax

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