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CDK5 Inhibitor Downregulates Mcl-1 and Sensitizes Pancreatic Cancer Cell Lines to Navitoclax

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-([1,1′-biphenyl]-4-yl)-N-(5-cyclobutyl-1H-pyrazol-3-yl)acetamide (analog 24), which selectively inhibited cyclin-dependent kinase...

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Autores principales: Kour, Smit, Rana, Sandeep, Contreras, Jacob I., King, Hannah M., Robb, Caroline M., Sonawane, Yogesh A., Bendjennat, Mourad, Crawford, Ayrianne J., Barger, Carter J., Kizhake, Smitha, Luo, Xu, Hollingsworth, Michael A., Natarajan, Amarnath
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The American Society for Pharmacology and Experimental Therapeutics 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6726458/
https://www.ncbi.nlm.nih.gov/pubmed/31467029
http://dx.doi.org/10.1124/mol.119.116855
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author Kour, Smit
Rana, Sandeep
Contreras, Jacob I.
King, Hannah M.
Robb, Caroline M.
Sonawane, Yogesh A.
Bendjennat, Mourad
Crawford, Ayrianne J.
Barger, Carter J.
Kizhake, Smitha
Luo, Xu
Hollingsworth, Michael A.
Natarajan, Amarnath
author_facet Kour, Smit
Rana, Sandeep
Contreras, Jacob I.
King, Hannah M.
Robb, Caroline M.
Sonawane, Yogesh A.
Bendjennat, Mourad
Crawford, Ayrianne J.
Barger, Carter J.
Kizhake, Smitha
Luo, Xu
Hollingsworth, Michael A.
Natarajan, Amarnath
author_sort Kour, Smit
collection PubMed
description 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-([1,1′-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.
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spelling pubmed-67264582019-10-30 CDK5 Inhibitor Downregulates Mcl-1 and Sensitizes Pancreatic Cancer Cell Lines to Navitoclax Kour, Smit Rana, Sandeep Contreras, Jacob I. King, Hannah M. Robb, Caroline M. Sonawane, Yogesh A. Bendjennat, Mourad Crawford, Ayrianne J. Barger, Carter J. Kizhake, Smitha Luo, Xu Hollingsworth, Michael A. Natarajan, Amarnath Mol Pharmacol Articles 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-([1,1′-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. The American Society for Pharmacology and Experimental Therapeutics 2019-10 2019-10 /pmc/articles/PMC6726458/ /pubmed/31467029 http://dx.doi.org/10.1124/mol.119.116855 Text en Copyright © 2019 by The Author(s) http://creativecommons.org/licenses/by-nc/4.0/ This is an open access article distributed under the CC BY-NC Attribution 4.0 International license (http://creativecommons.org/licenses/by-nc/4.0/) .
spellingShingle Articles
Kour, Smit
Rana, Sandeep
Contreras, Jacob I.
King, Hannah M.
Robb, Caroline M.
Sonawane, Yogesh A.
Bendjennat, Mourad
Crawford, Ayrianne J.
Barger, Carter J.
Kizhake, Smitha
Luo, Xu
Hollingsworth, Michael A.
Natarajan, Amarnath
CDK5 Inhibitor Downregulates Mcl-1 and Sensitizes Pancreatic Cancer Cell Lines to Navitoclax
title CDK5 Inhibitor Downregulates Mcl-1 and Sensitizes Pancreatic Cancer Cell Lines to Navitoclax
title_full CDK5 Inhibitor Downregulates Mcl-1 and Sensitizes Pancreatic Cancer Cell Lines to Navitoclax
title_fullStr CDK5 Inhibitor Downregulates Mcl-1 and Sensitizes Pancreatic Cancer Cell Lines to Navitoclax
title_full_unstemmed CDK5 Inhibitor Downregulates Mcl-1 and Sensitizes Pancreatic Cancer Cell Lines to Navitoclax
title_short CDK5 Inhibitor Downregulates Mcl-1 and Sensitizes Pancreatic Cancer Cell Lines to Navitoclax
title_sort cdk5 inhibitor downregulates mcl-1 and sensitizes pancreatic cancer cell lines to navitoclax
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6726458/
https://www.ncbi.nlm.nih.gov/pubmed/31467029
http://dx.doi.org/10.1124/mol.119.116855
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