XL388 is a selective inhibitor of mTOR with IC50 value of 9.9 nM [1].
mTOR, a member of the phosphatidylinositol 3-kinase (PI3K) cell survival pathway, plays an important role in the regulation of cell growth and proliferation by monitoring nutrient availability, cellular energy levels, oxygen levels, and mitogenic signals [1].
In MCF-7 cells, XL388 blocks mTORC1 phosphorylation of p70S6K with an IC50 value of 94 nM and mTORC2 phosphorylation of AKT with an IC50 value of 350 nM. When assayed alone, XL388 inhibits the viability of hematopoietic tumor cell lines in vitro. Also, XL388 synergizes with chemotherapeutics in cell-based assays to block cell viability [1].
XL388 shows robust antitumor activity in multiple xenograft models when dosed orally once daily in mice, especially in the MCF-7 xenograft model it shows > 100% tumor growth inhibition [1]. XL388 displays strong pharmacokinetics and good oral exposure in multiple species. Oral administration of XL388 to athymic nude mice implanted with MCF-7 xenograft tumors afforded significant and dose-dependent antitumor activity, which suggest that block of mTOR signaling is a viable target for antitumor activity [2].
References:
[1]. Nicole Miller. Abstract B146: XL388: A novel, selective, orally bioavailable mTORC1 and mTORC2 inhibitor that demonstrates pharmacodynamic and antitumor activity in multiple human cancer xenograft models. Mol Cancer Ther, 2009, 8(12 Suppl):B146.
[2].Takeuchi CS, Kim BG, Blazey CM, et al. Discovery of a Novel Class of Highly Potent, Selective, ATP-Competitive, and Orally Bioavailable Inhibitors of the Mammalian Target of Rapamycin (mTOR). J Med Chem, 2013, 56(6):2218-34.