PI3K is a clinically validated target for the treatment of cancer. During our search for novel chemical matter that selectively inhibit PI3K, we discovered a structural series based on the benzoxepin scaffold. Compounds in this class are potent and selective for the Class I PI3K isoforms. The inhibitors have shown good in vitro stability which has resulted in good preclinical pharmacokinetics. We will describe our ligand optimization efforts including the use of structure-guided hypotheses together with physicochemical property information to generate compounds that exclusively target the oncogenic PI3K-alpha isoform and had good in vivo anti-tumor activity.

Discovery of benzoxazepin PI3K inhibitors and optimization of p110-alpha selectivity

245th National Meeting (2013)

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