MTI-31 是一种有效的，具有口服活性的，且高度选择性的mTORC1和mTORC2抑制剂。MTI-31 高选择性作用于 mTOR，Kd为 0.20 nM。MTI-31 对 mTOR 的IC50为 39 nM。MTI-31可用于乳腺癌的研究。
| 生物活性 | MTI-31 is a potent, orally active and highly selective inhibitor ofmTORC1andmTORC2. MTI-31 is selective formTOR(Kd: 0.20 nM) versus PIK3CA, PIK3CB and PIK3G with >5,000 fold selectivity inmTORbinding assays. MTI-31 shows anIC50of 39 nM formTORin LANCE assay ofmTORsubstrate phosphorylation with 100 μM ATP. MTI-31 can be used for the research of breastcancer[1]. |
| IC50& Target[1] | mTOR 0.2 nM (Ki) | mTOR 39 nM (IC50, 100 μM ATP) | mTORC1 | mTORC2 |
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体外研究
(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[1].
MTI-31 (0.01-100 μM) elicits a potent and more substantial inhibition of cell growth than that of Rapamycin[1].
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)[1].
MTI-31-induced apoptosis requires mTORC2-regulated Bim- and GSK3 activity[1].
Cell Proliferation Assay[1] | 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[1] | 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). |
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体内研究
(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[1].
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)[2].
| Animal Model: | Female nude mice bearing tumors of MDA-MB-453, 786-O or HCC1806[1] | | 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).
In contrast, had limited efficacy in the HER2-/PIK3CAwt HCC1806 breast tumor model even at the highest 40 mg/kg. |
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| 运输条件 | Room temperature in continental US; may vary elsewhere. |
| 储存方式 | | Powder | -20°C | 3 years | | 4°C | 2 years | | In solvent | -80°C | 6 months | | -20°C | 1 month |
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| 溶解性数据 | In Vitro: DMSO : 8.33 mg/mL(17.55 mM;ultrasonic and warming and heat to 60℃) 配制储备液 | 1 mM | 2.1073 mL | 10.5363 mL | 21.0726 mL | | 5 mM | 0.4215 mL | 2.1073 mL | 4.2145 mL | | 10 mM | 0.2107 mL | 1.0536 mL | 2.1073 mL |
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此方案可获得 ≥ 0.83 mg/mL (1.75 mM，饱和度未知) 的澄清溶液。 以 1 mL 工作液为例，取 100 μL 8.3 mg/mL 的澄清 DMSO 储备液加到 900 μL20% 的 SBE-β-CD 生理盐水水溶液中，混合均匀。
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