SNS-032 (BMS-387032) is a selective inhibitor of CDK2 (IC50: 48 nM), exhibiting 10- and 20-fold selectivity over CDK1 and CDK4, respectively. It is also sensitive to CDK7 (IC50: 62 nM) and CDK9 (IC50: 4 nM), with no effect on CDK6.

CDK9:4 nM, CDK2:48 nM, CDK7:62 nM

SNS-032 demonstrates low sensitivity towards CDK1 and CDK4, with IC50 values of 480 nM and 925 nM, respectively. It effectively eradicates chronic lymphocytic leukemia cells in vitro, showing significant effectiveness regardless of prognostic indicators or previous treatments. In comparison to flavopiridol and roscovitine, SNS-032 exhibits superior potency, both in inhibiting RNA synthesis and inducing apoptosis. Its reversibility is notable, as the withdrawal of SNS-032 leads to the reactivation of RNA polymerase II, resynthesis of Mcl-1, and consequently, cell survival. Moreover, SNS-032 inhibits the formation of three-dimensional capillary networks in endothelial cells, completely halting U87 mg cell-mediated capillary formation in HUVECs and significantly reducing VEGF production in both cell lines, thereby preventing in vitro angiogenesis primarily by blocking VEGF. Preclinical studies reveal SNS-032's ability to induce cell cycle arrest and apoptosis in multiple cell lines by inhibiting CDKs 2, 7, and 9, highlighting its effectiveness regardless of human serum presence. It also triggers a dose-dependent increase in annexin V staining and caspase-3 activation, dephosphorylates serine 2 and 5 of RNA polymerase II, and reduces the expression of CDK2 and CDK9, alongside dephosphorylated CDK7.

SNS-032 prevents tumor cell-induced VEGF secretion in a tumor coculture model. [2] SNS-032, a new CDK inhibitor, is more selective and less cytotoxic and has been shown to prolong stable disease in solid tumors. [4]

Cell Titer-Glo (CTG) luminescent assay is performed to measure the growth curves of both HUVECs and U87 mg cells. U87 mg cells and HUVECs (2×103 cells/well) are seeded in a 96-well microplate in a final volume of 100 ml. After 24 hours, cells are treated with various doses of SNS-032 (0–0.5 mM) for 24, 48, or 72 hours. After completion of the treatment, 100 ml of CTG solution is added to each well and incubated for 20 minutes at room temperature in the dark. Lysate (50 ml) is transferred to a 96-well white plate, and luminescence is measured by POLARstar OPTIMA. Percent cell growth is calculated by considering 100% growth at the time of SNS-032 addition.(Only for Reference)