BAY 1112054: A Potent, Selective PTEFb/CDK9 Inhibitor with Notable Anti-Tumor Effects in Oncology

The cyclin-dependent kinase (CDK) family includes proteins that regulate the cell cycle and gene transcription, such as CDK9/PTEFb. Targeting PTEFb and RNA polymerase II is believed to deplete short-lived mRNA transcripts of vital proteins, leading to growth arrest and cell death in certain tumor cells. Unlike broad-spectrum CDK inhibitors that are in clinical trials, PTEFb-specific inhibitors have not been clinically tested.

BAY 1112054 is a potent and selective PTEFb-kinase inhibitor with a high level of specificity for PTEFb/CDK9 and minimal activity against other CDKs. It also demonstrates favorable selectivity against non-CDK kinases. This compound has shown significant anti-proliferative effects against various tumor cell lines with sub-micromolar IC-50 values.

In A549 tumor cells, BAY 1112054 induced a concentration-dependent decrease in RNA polymerase II phosphorylation, which was associated with a reduction in intracellular Mcl-1 protein levels. Additionally, the compound increased DNA fragmentation in HeLa cells after a 24-hour treatment.

In two mouse xenograft models, BAY 1112054 demonstrated efficacy at tolerable doses. Daily oral administration resulted in tumor stasis in MOLM-13 AML xenografts, with pharmacokinetic data indicating sustained unbound plasma levels above the cellular IC50. The compound's efficacy and tolerability were also confirmed in NCI-H82 SCLC xenografts, where treated tumors showed reduced RNA polymerase II phosphorylation and Mcl-1 levels.

The findings support the potential of BAY 1112054 as a first-in-class PTEFb/CDK9 inhibitor, suggesting that PTEFb selective inhibitors should be further evaluated for cancer treatment targeting the transcription of short-lived survival proteins.

Reference: Scholz A, et al. BAY 1112054, a potent and selective inhibitor of PTEFb/CDK9, exhibits significant anti-tumor activity. Proceedings of the AACR Annual Meeting, 2014; San Diego, CA. Cancer Res 2014;74(19 Suppl):Abstract nr 4538. doi:10.1158/1538-7445.AM2014-4538.