MTI-31

MTI-31 (LXI-15029) is a potent, orally active and highly selective inhibitor of mTORC1 and mTORC2 . MTI-31 is selective for mTOR ( K d : 0.20 nM) versus PIK3CA, PIK3CB and PIK3G with >5,000 fold selectivity in mTOR binding assays. MTI-31 shows an IC 50 of 39 nM for mTOR in LANCE assay of mTOR substrate phosphorylation with 100 μM ATP. MTI-31 can be used for the research of breast cancer In Vitro MTI-31 acts as a potent and selective inhibitor of mTOR enzymatic activity capable of targeting both mTORC1 and mTORC2 functions in cancer cells. MTI-31 (0.01-100 μM) elicits a potent and more substantial inhibition of cell growth than that of Rapamycin. Treatment with MTI-31 for 6 h demonstrates a dose-dependent inhibition of both the mTORC1 substrates P-S6K1(T389), P-S6(S235/6), P-4EBP1(T70) and mTORC2 substrate P-AKT(S473), achieving 50% inhibition at ≤0.12 μM in three representative tumor cell lines harboring mTOR pathway dysregulation (786-O renal, U87MG glioma and MDA-MB-453 breast). MTI-31-induced apoptosis requires mTORC2-regulated Bim- and GSK3 activity. MCE has not independently confirmed the accuracy of these methods. They are for reference only. Cell Proliferation AssayCell Line: MDA-MB-453 cells Concentration: 0.01, 0.1, 1, 10, 100 μM Incubation Time: 3 days Result: Significantly inhibited cellular proliferation after treatment for 3 days. Western Blot AnalysisCell Line: 786-O renal, U87MG glioma and MDA-MB-453 breast cells Concentration: 0.12, 0.37, 1.11, 3.33, 10 μM Incubation Time: 6 hours Result: Demonstrated a dose-dependent inhibition of both the mTORC1 substrates P-S6K1(T389), P-S6(S235/6), P-4EBP1(T70) and mTORC2 substrate P-AKT(S473). In Vivo MTI-31 is a potent mTOR inhibitor in vivo and elicits strong antitumor efficacy. MTI-31(5-40 mg/kg; orally) is efficacious in several tumor models harboring HER2+/PIK3CAmut and/or PTEN-deficiency exemplified by MDA-MB-453 and 786-O . Treatment of tumor bearing nude mice with orally administered MTI-31 inhibits growth of H1975 tumors (25 mg/kg/d; orally) or U87MG tumors (30 mg/kg/d; orally). MCE has not independently confirmed the accuracy of these methods. They are for reference only. Animal Model: Female nude mice bearing tumors of MDA-MB-453, 786-O or HCC1806 Dosage: 2.5, 5, 10, 20, 40 mg/kg for MDA-MB-453 and 786-O; 20 and 40 mg/kg for HCC1806 Administration: Treated orally via a once daily (qd) regimen Result: Was efficacious in several tumor models harboring HER2+/PIK3CAmut and/or PTEN-deficiency exemplified by MDA-MB-453 and 786-O. Demonstrated a dose proportional tumor growth inhibition (TGI) with a minimum efficacious dose (MED) of 5 mg/kg (>50% TGI, p Form:Solid IC50& Target:mTOR 0.2 nM (Ki) mTOR 39 nM (IC 50 , 100 μM ATP) mTORC1 mTORC2

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