Selective PTEFb/CDK9 Inhibition by BAY 1143572: Targeting MYC to Combat Tumors and Overcome Chemoresistance

The transcription factor PTEFb/CDK9 is pivotal in the production of brief-lived anti-apoptotic proteins such as MYC, which is a significant oncogene in various cancers and crucial for the growth and survival of cancer cells. The development of resistance to chemotherapy is also linked to these proteins. While pan-CDK inhibitors are in clinical trials, selective PTEFb inhibitors have not been clinically tested. We introduce BAY 1143572, a novel and selective inhibitor of PTEFb/CDK9, which is now in a Phase I trial.

BAY 1143572 exhibits strong and specific inhibition of PTEFb-kinase at low nanomolar concentrations, with at least 50 times more selectivity over other CDKs in enzymatic tests. It also demonstrates favorable selectivity against non-CDK kinases. The compound's potent enzymatic activity leads to a broad range of antiproliferative effects against various tumor cell lines with sub-micromolar IC-50 values. The compound inhibits the phosphorylation of RNA polymerase II and reduces MYC mRNA and protein levels, leading to apoptosis induction.

In vivo, BAY 1143572 has shown efficacy at well-tolerated doses in xenograft tumor models, with partial to complete remissions observed in models with different MYC gene alterations. The treatment leads to a temporary decrease in intratumoral MYC mRNA and protein levels and induces apoptosis. The inhibition of MYC mRNA in blood cells of treated rats suggests its potential as a pharmacodynamic marker. The compound's efficacy is enhanced when combined with other chemotherapeutic agents.

Our findings support the clinical development of BAY 1143572 for advanced cancer patients, especially for cancers reliant on MYC transcription and other short-lived survival proteins. The study is published in the proceedings of the American Association for Cancer Research's 106th Annual Meeting.