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Overview
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Background
OXA-01 is an ATP-competitive and selective inhibitor of both mTORC1 and mTORC2 with IC50 values of 29 nM and 7 nM, respectively [1]. The mammalian target of rapamycin (mTOR) is a serine/threonine kinase and exists in two complexes, mTORC1 and mTORC2. MTORC1 activation through PI3K and Akt controls cell growth and mTORC2 phosphorylates Akt, SGK1, and PKC to control cell survival and cytoskeletal organization [1]. OXA-01 is a dual inhibitor of mTORC1 and mTORC2, and inhibited mTOR kinase with IC50 value of 11 nM. In cell-based assays, OXA-01 inhibited mTOR signaling of phospho-4E-BP1 with IC50 value of 1.1 μM [1].In GEO colorectal xenograft model, the median plasma concentration of OXA-01 was 25.6 μM at 1 hour and 13.2 μM at 8 hours, and OXA-01 slowed tumor growth. In RIP-Tag2 pancreatic neuroendocrine tumors, OXA-01 reduced Akt, 4E-BP1 and S6K phosphorylation. OXA-01 also decreased cellular proliferation and increased apoptosis. OXA-01 reduced VEGF production, which was associated with decreased tumor angiogenesis [1].
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