MTI-31

本公司产品仅用于科研实验，不得用于人体或动物的临床与诊断

MTI-31（LXI-15029，mTOR 抑制剂-31）是一种新型有效的选择性 mTORC1/mTORC2 抑制剂，Kd 为 0.2 nM (mTOR)。

MTI-31 (LXI-15029, mTOR inhibitor-31) is a novel potent, selective mTORC1/mTORC2 inhibitor with Kd of 0.2 nM (mTOR), displays >5,000-fold selectivity over PIK3CA, PIK3CB and PIK3G; showed an IC50 value 39 nM in LANCE? assay of mTOR substrate phosphorylation; dose-dependently inhibits of both the mTORC1 substrates P-S6K1(T389), P-S6(S235/6), P-4EBP1(T70) and mTORC2 substrate P-AKT(S473) tumor cell lines harboring mTOR pathway dysregulation with IC50 of <0.12 uM; potently inhibited cell proliferation (IC50 <1 mmol/L) and in vivo tumor growth in multiple NSCLC models of EGFR/T790M, EML4-ALK, c-Met or KRAS (MED <10 mg/kg), also suppressed programmed death ligand 1 (PD-L1) in EGFR- and ALK-driven NSCLC, mediated in part by mTORC2/AKT/GSK3β-dependent proteasomal degradation.

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. Cell Proliferation Assay Cell 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 Analysis Cell 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).

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). 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<0.01) and a maximum tolerated dose (MTD) of 40 mg/kg (7-15% body weight loss without mortality).

LXI-15029 | mTOR inhibitor-31

PI3K/Akt/mTOR signaling

mTOR

mTOR

——

——

1567915-38-1

474.565

C26H30N6O3

>98% (HPLC)

In Vitro:?DMSO : 8.33 mg/mL (17.55 mM)

——

3-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-2-((S)-3-methylmorpholino)pyrido[2,3-d]pyrimidin-7-yl)-N-methylbenzamide

(-20℃)

With Ice Pack

≥ 2 years