Abstract
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.
Highlights
Colorectal cancer (CRC) continues to be a major health concern in the United States where it is currently the fourth most commonly diagnosed malignancy and the second leading cause of cancer related deaths [1]
With increasing evidence suggesting a role for cyclin-dependent kinase 5 (CDK5) in a variety of malignancies, we turned to The Cancer Genome Atlas (TCGA – http://cancergenome.nih. gov/) database to gain insight into CDK5 expression in patient populations
We investigated whether CDK5 mutation could possibly be contributing to its activity in CRC so we examined the mutational frequency of CDK5 in all The cancer genome atlas (TCGA) cancers
Summary
Colorectal cancer (CRC) continues to be a major health concern in the United States where it is currently the fourth most commonly diagnosed malignancy and the second leading cause of cancer related deaths [1]. CDKs are often categorized into two major groups, those that contribute to tumorigenesis through cell cycle control and those that regulate transcription [2,3,4]. One peculiar member of the CDK family that does not regulate transcription and only recently has been shown to contribute to cell cycle progression, is CDK5. Reports have identified CDK5 as a key player in non-neuronal functions including apoptosis, senescence, angiogenesis, insulin secretion, wound healing, and adhesion/migration [6]. These functions associated with CDK5 are believed to contribute to its role in tumorigenesis. CDK5 has been previously implicated in a number of cancers, including those of the pancreas [7, 8], thyroid [9, 10], prostate [11, 12], breast [13], lung [14], liver [15], and most recently as a tumor promoter in CRC [16]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
