Characterization of molecular and cellular functions of the cyclin‐dependent kinase CDK9 using a novel specific inhibitor

摘要: Background and Purpose The cyclin-dependent kinase CDK9 is an important therapeutic target but currently available inhibitors exhibit low specificity and/or narrow windows. Here we have used a new highly specific inhibitor, LDC000067 to interrogate gene control mechanisms mediated by CDK9. Experimental Approach The selectivity of was established in functional assays. Functions expression were assessed with vitro transcription experiments, single analyses genome-wide profiling. Cultures mouse embryonic stem cells, HeLa several cancer cell lines, along cells from patients acute myelogenous leukaemia also investigate cellular responses LDC000067. Key Results The for over other CDKs exceeded that the known flavopiridol DRB. inhibited ATP-competitive dose-dependent manner. Gene profiling treated demonstrated selective reduction short-lived mRNAs, including regulators proliferation apoptosis. Analysis de novo RNA synthesis suggested wide ranging positive role CDK9. At molecular level, reproduced effects characteristic inhibition such as enhanced pausing RNA polymerase II on genes and, most importantly, induction apoptosis cells. Conclusions Implications Our study provides framework mechanistic understanding inhibition. represents promising lead development clinically useful, inhibitors.