XL388

XL388 is a potent, selective, and ATP-competitive small molecule inhibitor of the mechanistic target of rapamycin (mTOR), targeting both the mTORC1 and mTORC2 complexes. Developed by Exelixis, XL388 was designed to provide more complete inhibition of the PI3K/AKT/mTOR pathway compared to first-generation rapalogs by directly blocking the mTOR kinase domain. This dual inhibition prevents the phosphorylation of downstream effectors such as p70S6K, 4E-BP1, and AKT (at the Ser473 site). While XL388 has demonstrated the ability to inhibit cell proliferation and S-phase entry in various cancer models, including glioblastoma, recent comparative studies have indicated it may be less effective than other second-generation inhibitors like Torin2 in suppressing cell migration and the self-renewal of cancer stem cells.