title: CDKI-71, a novel CDK9 inhibitor, is preferentially cytotoxic to cancer cells compared to flavopiridol.
abstract: Cancer cells appear to depend heavily on antiapoptotic proteins for survival and so targeted inhibition of these proteins has therapeutic potential. One innovative strategy is to inhibit the cyclin-dependent kinases (CDKs) responsible for the regulation of RNA polymerase II (RNAPII). In our study, we investigated the detailed cellular mechanism of a novel small-molecule CDK inhibitor (CDKI-71) in cancer cell lines, primary leukemia cells, normal B - & T- cells, and embryonic lung fibroblasts and compared the cellular and molecular responses to the clinical CDK inhibitor, flavopiridol. Like flavopiridol, CDKI-71 displayed potent cytotoxicity and caspase-dependent apoptosis induction that were closely associated with the inhibition of RNAPII phosphorylation at serine-2. This was caused by effective targeting of cyclinT-CDK9 and resulted in the downstream inhibition of Mcl-1. No correlation between apoptosis and inhibition of cell-cycle CDKs 1 and 2 was observed. CDKI-71 showed a 10-fold increase in potency in tumor cell lines when compared to MRC-5 human fibroblast cells. Significantly, CDKI-71 also demonstrated potent anti-chronic lymphocytic leukemia activity with minimal toxicity in normal B- and T-cells. In contrast, flavopiridol showed little selectivity between cancer and normal cells. Here, we provide the first cell-based evidence that flavopiridol induces DNA double-strand breaks: a fact which may explain why flavopiridol has such a narrow therapeutic window in preclinical and clinical settings. Taken together, our data provide a rationale for the development of selective CDK inhibitors as therapeutic agents and CDKI-71 represents a promising lead in this context.
authors.affiliation: School of Pharmacy and Centre for Biomolecular Sciences, University of Nottingham, University Park, Nottingham, United Kingdom.
authors.forename: Xiangrui
authors.initials: X
authors.lastname: Liu
authors.forename: Shenhua
authors.initials: S
authors.lastname: Shi
authors.forename: Frankie
authors.initials: F
authors.lastname: Lam
authors.forename: Chris
authors.initials: C
authors.lastname: Pepper
authors.forename: Peter M
authors.initials: PM
authors.lastname: Fischer
authors.forename: Shudong
authors.initials: S
authors.lastname: Wang
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D042863:Cyclin-Dependent Kinase 9 / Q000037:antagonists & inhibitors*; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D005419:Flavonoids / Q000494:pharmacology*; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy; D010880:Piperidines / Q000494:pharmacology*; D013449:Sulfonamides / Q000627:therapeutic use*; D000096926:Benzenesulfonamides
chemical_list: D000970:Antineoplastic Agents; D042863:Cyclin-Dependent Kinase 9; D004791:Enzyme Inhibitors; D005419:Flavonoids; D010880:Piperidines; D013449:Sulfonamides; C569861:3-(5-cyano-4-(4-methyl-2-(methylamino)thiazol-5-yl)pyrimidin-2-ylamino)benzenesulfonamide; D000096926:Benzenesulfonamides; C077990:alvocidib; C467969:CDK9 protein, human