Dual mTOR and PI3K Inhibitor – X-480

Phosphoinositide 3-kinase (PI3K) is a part of a class of lipid kinases that is deregulated in greater than 50% of human cancers. Deregulation of PI3K signaling is thought to occur in two different ways including an increase in PI3K signaling resulting from activating gene mutations, amplification and overexpression of PI3Ks or through upstream receptors that activate PI3K. The PI3K pathway is part of the PI3/AKT/mTOR pathway and is involved in angiogenesis, cell growth, differentiation, and survival. The PI3K pathway is one of the most frequently deregulated pathways in cancer.

Xcovery’s X-480 is a potent pan inhibitor of the pathway blocking signaling through both PI3K and mTOR. X-480 alone or in combination with other targeted therapies may be effective in multiple solid tumor types where the PI3K pathway is deregulated. These include breast, colon, NSCLC, glioblastoma, endometrial, ovarian, and other tumor types. Signaling through the Ras pathway and the PI3K pathway converge on several critical processes (proliferation, metabolism, protein synthesis and cell survival) that maintain tumor homeostasis. Because these pathways converge on these critical tumor survival processes, activation of one pathway can be an important means of resistance to drugs directed at the other pathway. As such, X-480 may restore sensitivity to tumors (e.g. NSCLC) that have become resistant to Ras pathway inhibition by EGFR inhibitors by deregulating PI3K activity. X-480 is in pre-clinical development.