CDK5 inhibitor downregulates Mcl-1 and sensitizes pancreatic cancer cell lines to navitoclax

Smit Kour, Sandeep Rana, Jacob I. Contreras, Hannah M. King, Caroline M. Robb, Yogesh A. Sonawane, Mourad Bendjennat, Ayrianne J. Crawford, Carter J. Barger, Smitha Kizhake, Xu Luo, Michael A. Hollingsworth, Amarnath Natarajan

Research output: Contribution to journalArticle

3 Scopus citations

Abstract

Developing small molecules that indirectly regulate Mcl-1 function has attracted a lot of attention in recent years. Here, we report the discovery of an aminopyrazole, 2-([1,19-biphenyl]-4-yl)-N-(5-cyclobutyl-1H-pyrazol-3-yl)acetamide (analog 24), which selectively inhibited cyclin-dependent kinase (CDK) 5 over CDK2 in cancer cell lines. We also show that analog 24 reduced Mcl-1 levels in a concentration-dependent manner in cancer cell lines. Using a panel of doxycycline inducible cell lines, we show that CDK5 inhibitor 24 selectively modulates Mcl-1 function while the CDK4/6 inhibitor 6-acetyl-8-cyclopentyl-5-methyl-2-(5-(piperazin-1-yl)pyridin-2-ylamino)pyrido[2,3-day]pyrimidin-7(8H)-one does not. Previous studies using RNA interference and CRISPR showed that concurrent elimination of Bcl-xL and Mcl-1 resulted in induction of apoptosis. In pancreatic cancer cell lines, we show that either CDK5 knockdown or expression of a dominant negative CDK5 when combined with Bcl2 inhibitor results in synergistic induction of apoptosis. Moreover, concurrent pharmacological perturbation of Mcl-1 and Bcl-xL in pancreatic cancer cell lines using a CDK5 inhibitor analog 24 that reduced Mcl-1 levels and 4-(4-{[2-(4-chlorophenyl)-5,5-dimethyl-1-cyclohexen-1-yl]methyl}-1-piperazinyl)-N-[(4-{[(2R)-4-(4-morpholinyl)-1-(phenylsulfanyl)-2-butanyl]amino}-3-[(trifluoromethyl)sulfonyl]phenyl)sulfonyl] benzamide (navitoclax), a Bcl-2/Bcl-xL/Bcl-w inhibitor, resulted in synergistic inhibition of cell growth and induction of apoptosis. In conclusion, we demonstrate targeting CDK5 will sensitize pancreatic cancers to Bcl-2 inhibitors. SIGNIFICANCE STATEMENT Mcl-1 is stabilized by CDK5-mediated phosphorylation in pancreatic ductal adenocarcinoma, resulting in the deregulation of the apoptotic pathway. Thus, genetic or pharmacological targeting of CDK5 sensitizes pancreatic cancers to Bcl-2 inhibitors, such as navitoclax.

Original languageEnglish (US)
Pages (from-to)419-429
Number of pages11
JournalMolecular pharmacology
Volume96
Issue number4
DOIs
StatePublished - Oct 2019

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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    Kour, S., Rana, S., Contreras, J. I., King, H. M., Robb, C. M., Sonawane, Y. A., Bendjennat, M., Crawford, A. J., Barger, C. J., Kizhake, S., Luo, X., Hollingsworth, M. A., & Natarajan, A. (2019). CDK5 inhibitor downregulates Mcl-1 and sensitizes pancreatic cancer cell lines to navitoclax. Molecular pharmacology, 96(4), 419-429. https://doi.org/10.1124/mol.119.116855