Aminopyrazole based CDK9 PROTAC sensitizes pancreatic cancer cells to venetoclax

Hannah M. King, Sandeep Rana, Sydney P. Kubica, Jayapal Reddy Mallareddy, Smitha Kizhake, Edward L. Ezell, Muhammad Zahid, Michael J. Naldrett, Sophie Alvarez, Henry C.H. Law, Nicholas T. Woods, Amarnath Natarajan

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Article number128061
JournalBioorganic and Medicinal Chemistry Letters
Volume43
DOIs
StatePublished - Jul 1 2021

Keywords

  • Aminopyrazole
  • CDK
  • Cancer
  • PROTAC
  • Venetoclax

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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