Characterization of CDK(5) inhibitor, 20-223 (aka CP668863) for colorectal cancer therapy
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Caroline M. Robb1, Smit Kour1, Jacob I. Contreras1, Ekta Agarwal1, Carter J. Barger1, Sandeep Rana1, Yogesh Sonawane1, Beth K. Neilsen1, Margaret Taylor1, Smitha Kizhake1, Rhishikesh N. Thakare2, Sanjib Chowdhury3, Jing Wang1,4, Jennifer D. Black1,4, Michael A. Hollingsworth1,4, Michael G. Brattain1,4,* and Amarnath Natarajan1,2,4
1Eppley Institute for Research in Cancer, University of Nebraska Medical Center, 985950 Nebraska Medical Center, Omaha, Nebraska 68198-5950, USA
2Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, Nebraska 68198-5950, USA
3Section of Gastroenterology, Department of Medicine, Boston University Medical Center, Boston, Massachusetts 02118, USA
4Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska 68198-5950, USA
Amarnath Natarajan, email: [email protected]
Keywords: colorectal cancer (CRC); cyclin-dependent kinase (CDK); CDK inhibitor
Received: September 06, 2017 Accepted: November 10, 2017 Published: December 28, 2017
Colorectal cancer (CRC) remains one of the leading causes of cancer related deaths in the United States. Currently, there are limited therapeutic options for patients suffering from CRC, none of which focus on the cell signaling mechanisms controlled by the popular kinase family, cyclin dependent kinases (CDKs). Here we evaluate a Pfizer developed compound, CP668863, that inhibits cyclin-dependent kinase 5 (CDK5) in neurodegenerative disorders. CDK5 has been implicated in a number of cancers, most recently as an oncogene in colorectal cancers. Our lab synthesized and characterized CP668863 – now called 20-223. In our established colorectal cancer xenograft model, 20-223 reduced tumor growth and tumor weight indicating its value as a potential anti-CRC agent. We subjected 20-223 to a series of cell-free and cell-based studies to understand the mechanism of its anti-tumor effects. In our hands, in vitro 20-223 is most potent against CDK2 and CDK5. The clinically used CDK inhibitor AT7519 and 20-223 share the aminopyrazole core and we used it to benchmark the 20-223 potency. In CDK5 and CDK2 kinase assays, 20-223 was ~3.5-fold and ~65.3-fold more potent than known clinically used CDK inhibitor, AT7519, respectively. Cell-based studies examining phosphorylation of downstream substrates revealed 20-223 inhibits the kinase activity of CDK5 and CDK2 in multiple CRC cell lines. Consistent with CDK5 inhibition, 20-223 inhibited migration of CRC cells in a wound-healing assay. Profiling a panel of CRC cell lines for growth inhibitory effects showed that 20-223 has nanomolar potency across multiple CRC cell lines and was on an average >2-fold more potent than AT7519. Cell cycle analyses in CRC cells revealed that 20-223 phenocopied the effects associated with AT7519. Collectively, these findings suggest that 20-223 exerts anti-tumor effects against CRC by targeting CDK 2/5 and inducing cell cycle arrest. Our studies also indicate that 20-223 is a suitable lead compound for colorectal cancer therapy.
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