A novel Cdk9 inhibitor preferentially targets tumor cells and synergizes with fludarabine.

Cdk9 is a key elongation factor for RNA transcription and functions by phosphorylating the C-terminal domain of RNA polymerase II. Here we present direct evidence that cdk9 is important for cancer cell survival and describe the characterization of the potent cdk9 inhibitor CDKI-73 in primary human leukemia cells. CDKI-73 induced caspase-dependent apoptosis that was preceded by dephosphorylation of cdk9 and serine 2 of RNA polymerase II.

Synthesis, structure-activity relationship and biological evaluation of 2,4,5-trisubstituted pyrimidine CDK inhibitors as potential anti-tumour agents.

A series of 2,4,5-trisubstituted pyrimidines have been synthesised and characterised, which exhibited potent CDK inhibition and anti-proliferative activities. The structure-activity relationship is analysed and a rational for CDK9 selectivity is discussed. Compound 9s, possessing appreciable selectivity for CDK9 over other CDKs, is capable of activating caspase 3, reducing the level of Mcl-1 anti-apoptotic protein, and inducing cancer cell apoptosis.

Synthesis and biological evaluation of imidazo[4,5-b]pyridine and 4-heteroaryl-pyrimidine derivatives as anti-cancer agents.

A series of N-phenyl-imidazo[4,5-b]pyridin-2-amines, 4-indazolyl-N-phenylpyrimidin-2-amines and N-phenyl-4-pyrazolo[3,4-b]pyridin-pyrimidin-2-amines have been synthesized. Their anti-proliferative activities were tested in HCT-116 human colon carcinoma and MCF-7 breast carcinoma cell lines. Many exhibited potent anti-proliferative and CDK9 inhibitory activities.