Optimized from the purine template of seliciclib, CCT068127 exhibits greater potency and selectivity against purified CDK2 and CDK9 and superior antiproliferative activity against human colon cancer and melanoma cell lines.
Further mechanistic study showed that over-expression of NPTX1 inhibited the expression of cyclin A2 and CDK2 in colon cancer cells, thereby regulating the Rb-E2F signaling.
Increased CDK2 activity decreases risk in colon cancer, but elevates poor outcome two- to fivefold in specific tumors, including low grade glioma, kidney, thyroid, adrenocortical and prostate cancer.
As revealed by Western blot, the expression of CDK2 and Cyclin D1 was down-regulated in all three Vglycin-treated colon cancer cells, indicating that the CDK2/Cyclin D1 cell cycle pathway involved in the initiation and progression of colon cancer.
Among the compounds synthesized, compound 8l displayed potent CDK2 and CDK5 inhibitory activities with low nanomolar ranges (IC<sub>50</sub>=2.1 and 4.8nM, respectively) and showed moderate cytotoxicity in HCT116 colon cancer and MCF7 breast cancer cell lines.
Transforming growth factor beta 1 increases the stability of p21/WAF1/CIP1 protein and inhibits CDK2 kinase activity in human colon carcinoma FET cells.