Abstract B146: XL388: A novel, selective, orally bioavailable mTORC1 and mTORC2 inhibitor that demonstrates pharmacodynamic and antitumor activity in multiple human cancer xenograft models

Abstract

Abstract Background: The mTOR kinase exists in at least two distinct kinase complexes, mTORC1 and mTORC2 which collectively regulate cell growth, proliferation, survival, autophagy, and angiogenesis. Derivatives of the macrolide antibiotic rapamycin have shown encouraging clinical activity as cancer therapeutics; however, these molecules only partially inhibit mTORC1 and mTORC2 activity. Here we provide the first pre-clinical description of XL388, a selective and orally bioavailable small-molecule ATP-competitive inhibitor of mTORC1 and mTORC2 that demonstrates pharmacodynamic and anti-tumor activity in multiple human cancer xenograft models. Methods: The in vitro inhibition of mTORC1 and mTORC2 by XL388 was assayed using purified, recombinant mTOR/G L/raptor kinase and mTORC2 immunoprecipitated from cells, respectively. mTORC1 and mTORC2 substrate phosphorylation and pharmacodynamic activity were measured by phosphospecific immunoblot of lysates prepared from XL388-treated cancer cells or from xenograft tumor lysates prepared from XL388-treated animals. Cancer cell viability was determined by measuring cellular ATP concentrations or the disruption of cell membrane integrity. Synergy of XL388 with chemotherapeutics was measured by the combination index (CI) method as established by Chou and Talalay (1984). XL388 in vivo efficacy and pharmacodynamic studies were performed in nude mice bearing human tumor xenografts and dosed orally with XL388. Results and Conclusions: XL388 inhibits mTORC1 and mTORC2 in vitro with IC50 values of 8 nM and 166 nM, respectively. In MCF-7 cells, XL388 blocks mTORC1 phosphorylation of p70S6K (T389) with an IC50 value of 94 nM and blocks mTORC2 phosphorylation of AKT (S473) with an IC50 value of 350 nM. In vitro, XL388 inhibits the viability of solid and hematopoietic tumor cell lines when assayed as a single agent. XL388 also synergizes with chemotherapeutics in cell-based assays to block cell viability. When dosed orally once daily in mice, XL388 shows robust anti-tumor activity in multiple xenograft models including > 100% tumor growth inhibition in the MCF-7 xenograft model. Taken together, these data indicate that XL388 may have broad utility in cancer therapy both as a single agent and in combination with chemotherapeutics. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B146.