Characterization of the Activity of the PI3K/mTOR Inhibitor XL765 (SAR245409) in Tumor Models with Diverse Genetic Alterations Affecting the PI3K Pathway

Activation of the PI3K pathway is a frequent occurrence in human tumors and is thought to promote, growth, survival and resistance to diverse therapies. Here we report pharmacological characterization of the pyridopyrimidinone derivative, XL765 (SAR245409), a potent and highly selective pan inhibitor of Class I PI3Ks (alpha, beta, gamma, and delta) with activity against mTOR. Broad kinase selectivity profiling of >130 protein kinases revealed that XL765 is highly selective for Class I PI3Ks and mTOR over other kinases. In cellular assays, XL765 inhibits the formation of PIP3 in the membrane, and inhibits phosphorylation of AKT, p70S6K and S6 phosphorylation in multiple tumor cell lines with different genetic alterations impacting the PI3K pathway. In a panel of tumor cell lines, XL765 inhibits proliferation with a wide range of potencies, with evidence of an impact of genotype on sensitivity. In mouse xenograft models, oral administration of XL765 results in dose-dependent inhibition of phosphorylation of AKT, p70S6K, and S6 with a duration of action of approximately 24 h. Repeat dose administration of XL765 results in significant tumor growth inhibition in multiple human xenograft models in nude mice that is associated with anti-proliferative, anti-angiogenic, and pro-apoptotic effects.