Advancements in Prostate Cancer Therapy: The Potential of a Selective CDK9 Inhibitor

The study focused on the development of a treatment for castration-resistant prostate cancers (CRPCs), which are unresponsive to hormone therapy but still reliant on the androgen receptor (AR) and transcription factors like MYC. Researchers utilized small molecule microarrays (SMMs) to discover compounds that interact with ARv7, a variant of AR linked to resistance. Through this process, they identified a compound, KI-ARv3, which inhibits CDK9, a cyclin-dependent kinase that is a key co-factor for transcription processes in cancer cells.

CDK9 is crucial for AR and MYC's function, and its inhibition can potentially disrupt oncogenic transcription programs. However, the challenge is to achieve a therapeutic effect without affecting normal transcription processes. The researchers optimized KI-ARv3 to create KB-00130742, a more potent CDK9 inhibitor with high selectivity and oral bioavailability. This compound showed significant anti-tumor effects in CRPC and other MYC-dependent cancers, rapidly reducing the transcription and expression of AR-driven genes.

The study concluded that KB-00130742 is a promising therapeutic agent for treating CRPC by targeting the dependency on AR and oncogenic transcription, with well-tolerated oral administration and significant tumor growth reduction in preclinical models. The findings were presented at the 2020 Annual Meeting of the American Association for Cancer Research by the research team led by André Richters and David Freeman.