Rational Design\nof a Novel 6<i>H</i>‑Benzo[<i>c</i>]chromen\nSeries as Selective PI3Kα Inhibitors

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