title: In vitro antitumor mechanism of a novel cyclin-dependent kinase inhibitor CDKI-83.
abstract: Cancer is regarded as a proliferative disorder. Inhibition of cyclin-dependent kinases (CDKs), which are the key regulators of the cell-cycle and RNA transcription, represents an attractive strategy for cancer therapy. In this study, we report the cellular mechanistic investigation of CDKI-83, a K                         (i)-nanomolar CDK9 inhibitor. The compound shows effective anti-proliferative activity in human tumour cell lines with GI(50) <1 μM, and is capable of inducing apoptosis in A2780 human ovarian cancer cells as determined by the activated caspase-3, Annexin V/PI double staining and accumulated cells at the sub-G1 phase of cell-cycle. While A2780 cells were arrested in G(2)/M phase with CDKI-83 treatment, phosphorylation at Thr(320) of PP1α was significantly reduced, indicating CDK1 inhibition. Importantly, this compound reduced phosphorylation at Ser-2 of RNA polymerase II (RNAPII) by inhibiting cellular CDK9 activity, and down-regulated Mcl-1 and Bcl-2. These results suggest that combined inhibition of CDK9 and CDK1 may result in the effective induction of apoptosis and CDKI-83 has the potential to be developed as an anti-cancer agent.
authors.affiliation: School of Pharmacy and Centre for Biomolecular Sciences, University of Nottingham, University Park, Nottingham, NG7 2RD, UK.
authors.forename: Xiangrui
authors.initials: X
authors.lastname: Liu
authors.forename: Frankie
authors.initials: F
authors.lastname: Lam
authors.forename: Shenhua
authors.initials: S
authors.lastname: Shi
authors.forename: Peter M
authors.initials: PM
authors.lastname: Fischer
authors.forename: Shudong
authors.initials: S
authors.lastname: Wang
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D016203:CDC2 Protein Kinase / Q000037:antagonists & inhibitors*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D042863:Cyclin-Dependent Kinase 9 / Q000037:antagonists & inhibitors*; D006801:Humans; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D013449:Sulfonamides / Q000494:pharmacology*
chemical_list: C574987:4-(4-methyl-2-(methylamino)thiazol-5-yl)-2-(4-methyl-3-(morpholinosulfonyl)phenylamino)pyrimidine-5-carbonitrile; D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013449:Sulfonamides; D016203:CDC2 Protein Kinase; C467969:CDK9 protein, human; D042863:Cyclin-Dependent Kinase 9