| SNS-032 is a potent and selective cyclin-dependent kinase (CDK) inhibitor of CDK1, CDK2, CDK4, CDK7 and CDK9 with IC50 values of 480, 38, 925, 62 and 4 nM, respectively. SNS-032 concentrations (0.1-1μM) significantly induces chronic lymphocytic leukemia (CLL) cell death in a concentration-dependent manner, which reaches a maximum at 0.3 μM (82.2 %). SNS-032 (0.3 μM) only induces 14.5% cell death in mononuclear cells isolated from healthy donors, compared with a 73.8% cell death inductions in a set of 8 CLL samples. Moreover, SNS-032 induces a rapid concentration-dependent decrease in the mRNA levels of Mcl-1 in CLL cells.[1,2] SNS-032 (100 nM) decreases HUVECs cells growth by almost two-fold (150% and 200%) at 48 and 72 hours, respectively. Higher doses of SNS-032 (300 and 500 nM) completely inhibit the growth of HUVECs cells at 48 hours. SNS-032 inhibits endothelial tube formation by 27%, 65% and > 90% at 100, 300 and 500 nM, respectively. Besides, SNS-032 treatment inhibits 36%, 50%, and 60% of endothelial cell migration at 100, 300 and 500 nM, respectively. The treatment of SNS-032 at 300 nM for 24 hours markedly reduces (72%) the secretion of vascular endothelial growth factor (VEGF) by U87MG cells.[3] In A2780 human ovarian carcinoma xenograft model, SNS-032 has antitumor activity at all three doses (18, 36 and 48 mg/kg). At the low 18 mg/kg dose, SNS-032 shows minor tumor regression with a growth delay of 2.1 log cell kill units (LCK). At the higher 36 and 48 mg/kg doses, SNS-032 shows rapid, significant tumor regression and growth delays of ＞5.6 LCK and ＞6.5 LCK, respectively.[1] In p16-null multiple intestinal neoplasia (Min) mice, SNS-032 is well tolerated and reduces colon tumor burden to 36% of that in carrier-treated mice. In Ink4a/Arf-null mice, SNS-032 treatment reduces the intestinal tumor number to 25% and intestinal tumor burden to 16% of carrier-treated mice.[4] |
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