Roscovitine

A potent and selective CDK inhibitor with IC50 of 0.2 uM, 0.65 uM, and 0.7 uM for CDK5, Cdc2, and CDK2, respectively; weakly inhibits ERK1 and ERK2 (IC50=34 uM and 14 uM), poorly inhibits CDK4/cyclin D1 and CDK6/cyclin D2 (IC50>100 uM) ; suppresses the proliferation of mammalian cell lines with an average IC50 of 16 uM; significantly inhibits growth of The Ewing's sarcoma family of tumors (ESFT) xenografts.Lung Cancer Phase 2 Clinical (In Vitro) : (R) -Roscovitine (Seliciclib) displays high efficiency and high selectivity towards some cyclin-dependent kinases. The kinase specificity of Seliciclib is investigated with 25 highly purified kinases (including protein kinase A, G and C isoforms, myosin light-chain kinase, casein kinase 2, IR tyrosine kinase, c-src, v-abl) . Most kinases are not significantly inhibited by (R) -Roscovitine. Cdc2, Cdk2, and Cdk5 only are substantially inhibited (IC50 values of 0.65, 0.7, and 0.2 μM, respectively) . Cdk4k and Cdk6 are very poorly inhibited by (R) -Roscovitine (IC50>100 μM) . Extracellular regulated kinases erk1 and erk2 are inhibited with an IC50 of 34 μM and 14 μM, respectively. (R) -Roscovitine inhibits the proliferation of mammalian cell lines with an average IC50 of 16 μM. (R) -Roscovitine (Seliciclib) decreases the level of CDK5 and p35 with upregulation of E-cadherin, but downregulation of Vimentin and Collagen IV. Moreover, (R) -Roscovitine inhibits the ability of high glucose cultured NRK52E cells to migrate and invade. (In Vivo) :Compare with normal controls, (R) -Roscovitine (Seliciclib) downregulates phosphorylated ERK1/2 and PPARγ with concomitant increase in E-cadherin, but decrease in Vimentin and Collagen IV. Correspondingly, (R) -Roscovitine decreases renal tubulointerstitial fibrosis of diabetic rats. (R) -Roscovitine is effective in decreasing tubulointerstitial fibrosis via the ERK1/2/PPARγ pathway in diabetic rats. (R) -Roscovitine (Seliciclib) (16.5 mg/kg) significantly reduces the rate of tumor growth and increases survival of treated mice. Strikingly, (R) -Roscovitine treatment leads to complete tumor disappearance in one mouse (25%) ; moreover, no tumor regrowth in this mouse is found 5 months after completion of the treatment. Mouse weights do not differ significantly between mice treated with (R) -Roscovitine and control mice, and behavioral differences between the two groups are also negligible. These results suggest that (R) -Roscovitine can be used effectively as a selective tumor growth inhibitor in HPV+ head and neck cancer.