Rational Design of a Novel 6<i>H</i>-Benzo[<i>c</i>]chromen Series as Selective PI3Kα Inhibitors

The phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) signaling pathway is a frequently dysregulated pathway in human cancer, and PI3Kα is one of the most frequently mutated kinases in human cancer. A selective PI3Kα inhibitor may provide the opportunity to spare patients the side effects associated with broader inhibition of the class I PI3K family. Here, we describe our efforts to discover a novel series of selective PI3Kα inhibitors using structure-based drug design and molecular docking to inform the design of 6<i>H</i>-benzo[<i>c</i>]chromen inhibitors. XJTU-L453 (<b>21</b>) was identified with PI3Kα inhibitory potency and unique selectivity over other PI3K isoforms and all other kinases tested. Further evaluation of pharmacokinetic properties and in vivo efficacy led to the identification of the preclinical potential of XJTU-L453 (<b>21</b>).