A triple action CDK4/6-PI3K-BET inhibitor with augmented cancer cell cytotoxicity

The PI3K-AKT-mTOR pathway has been at the center of anti-cancer drug development 1 , 2 , but targeted inhibition of PI3K kinase activity is proven to provide a limited therapeutic effect and is often followed by the development of resistance to the drug 3 . This limitation could in part be alleviated through concurrently inhibiting multiple pathological pathways characterized by synthetic lethality relationship. For example, beneficial effects in metastatic breast cancer are observed when inhibition of PI3K is combined with BET proteins inhibition 4 . While the need for combinations of single agent targeted therapies has become clear, this approach commonly requires dose reduction of the individual agents due to additive toxicity that may compromise efficacy 5 .