Abstract DDT02-01: Discovery of GDC-0077, a highly isoform selective inhibitor of PI3Kα that promotes selective loss of mutant-p110α

PIK3CA, the gene that encodes for the p110α catalytic subunit of phosphatidylinositol-3-kinase (PI3Kα), is frequently mutated in cancer, with activating and transforming mutations of PIK3CA occurring in approximately 17% of cancers diagnosed annually. The narrow therapeutic index of PI3K inhibitors evaluated in the clinic thus far may be due to insufficient selectivity for PI3K isoform or mutant oncogenic driver. We report the results of our efforts directed at improving efficacy and safety of a class of benzoxazepin inhibitors of PI3K. A structure-, property-, and phenotype-guided strategy directed at high PI3K-isoform and PIKK-family selectivity, as well as a distinct cellular mechanism of action, culminated in the discovery of GDC-0077. Differences in primary and tertiary structure among PI3K isoforms were leveraged to achieve >300-fold selective inhibition of the PI3Kα isoform over the β, δ, and γ isoforms in biochemical assays. Very high selectivity over PIKK-family proteins such as mTOR, DNA-PK and VPS34 was also achieved through this process. In vitro and in vivo data indicate that GDC-0077 operates by a mechanism that promotes the selective degradation of “hotspot” p110α mutants (H1047R, E545K). Treatment of nude mice bearing PIK3CA-mutant breast tumor xenografts with oral GDC-0077 resulted in tumor regressions at well-tolerated doses. Together, the high degree of isoform selectivity, selective degradation of mutant-p110α, and in vivo PK/efficacy support the clinical evaluation of GDC-0077 as a treatment for patients with locally advanced or metastatic, PIK3CA-mutant cancer.

Citation Format: Steven T. Staben. Discovery of GDC-0077, a highly isoform selective inhibitor of PI3Kα that promotes selective loss of mutant-p110α [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr DDT02-01. doi:10.1158/1538-7445.AM2017-DDT02-01