MTI-31
(Synonyms: LXI-15029) 目录号 : GC64304
MTI-31是一种强效的高选择性mTORC1和mTORC2抑制剂（Kd: 0.20±0.04nmol/L），IC50值为39±1nmol/L。
Cas No.:1567915-38-1
Sample solution is provided at 25 µL, 10mM.
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MTI-31 is a potent and highly selective inhibitor of mTORC1 and mTORC2 (Kd: 0.20±0.04 nmol/L), with IC50 value of 39±1nmol/L[1]. MTI-31 has a potent mTOR binding affinity with >5000-fold selectivity over the related PI3K family isoforms[1]. MTI-31 demonstrates broad-spectrum antiviral activity against SARS-CoV-2 variants of concern and other coronaviruses in primary human airway epithelial cultures[2]. MTI-31 has been used in anti-tumor and anti-viral studies[1-2].
In vitro, MTI-31 can effectively inhibit cell proliferation (IC50 <1μmol/L) in various non-small cell lung cancer cell models including HCC827, PC9, H1975, H1993 and A549 cell lines[3]. MTI-31 treatment (≤0.12μmol/L) of the three representative tumor cell lines with dysregulated mTOR pathways (786-O renal cancer, U87MG glioma, and MDA-MB-453 breast cancer cells) resulted in dose-dependent inhibition of mTORC1 substrates P-S6K1 (T389), P-S6 (S235/6), P-4EBP1 (T70) as well as the mTORC2 substrate P-AKT (S473) which achieved 50% inhibition after 6 hours[1]. The combined treatment of MTI-31(0.1µmol/L) and RAD001(0.1µmol/L) for 6h significantly inhibited the proliferation and invasion of 786-O cells, up-regulated the expression of LC3 and activated the autophagy pathway[4].
In vivo, oral administration of 15mg/kg MTI-31 and 7.5mg/kg MRTX849 for 7 days significantly inhibited tumor growth and reduced tumor angiogenesis and collagen deposition in the KRAS mutant lung orthotopic xenograft mouse model[5]. In a mouse model of KRAS lung cancer, daily oral treatment with 10, 20, and 40mg/kg MTI-31 produced dose-dependent tumor suppression and strongly suppressed mTOR biomarker expression during 35 days[3].
References:
[1]Qian J, Chen Y, Meng T, et al. Molecular regulation of apoptotic machinery and lipid metabolism by mTORC1/mTORC2 dual inhibitors in preclinical models of HER2+/PIK3CAmut breast cancer[J]. Oncotarget, 2016, 7(41): 67071.
[2]van der Horst D, Carter-Timofte M E, Danneels A, et al. Large-scale deep learning identifies the antiviral potential of PKI-179 and MTI-31 against coronaviruses[J]. Antiviral Research, 2024, 231: 106012.
[3]Zhang Q, Zhang Y, Chen Y, et al. A novel mTORC1/2 inhibitor (MTI-31) inhibits tumor growth, epithelial–mesenchymal transition, metastases, and improves antitumor immunity in preclinical models of lung cancer[J]. Clinical Cancer Research, 2019, 25(12): 3630-3642.
[4] Zhang W, Yang C, Zou L, et al. Combining MTI-31 with RAD001 inhibits tumor growth and invasion of kidney cancer by activating autophagy[J]. Journal of Applied Genetics, 2024, 65(1): 103-112.
[5] Zhang Y, Liu L, Pei J, et al. Tissue factor overexpression promotes resistance to KRAS-G12C inhibition in non-small cell lung cancer[J]. Oncogene, 2024, 43(9): 668-681.
MTI-31是一种强效的高选择性mTORC1和mTORC2抑制剂（Kd: 0.20±0.04nmol/L），IC50值为39±1nmol/L[1]。MTI-31具有强有力的mTOR结合亲和力，选择性是PI3K相关家族亚型的5000倍[1]。在原代人气道上皮培养物中，MTI-31显示出对SARS-CoV-2高关注变异株和其他冠状病毒的广谱抗病毒活性[2]。MTI-31已用于抗肿瘤和抗病毒研究[1-2]。
在体外，MTI-31能有效抑制包含HCC827、PC9、H1975、H1993和A549细胞系在内的多种非小细胞肺癌细胞模型的增殖（IC50 <1μmol/L）[3]。MTI-31（≤0.12μmol/L）处理mTOR通路异常的三种代表肿瘤细胞系（786-O肾癌细胞，U87MG胶质瘤细胞和MDA-MB-453乳腺癌细胞）6小时后，导致mTORC1底物P-S6K1（T389）, P-S6（S235/6）, P-4EBP1（T70）和mTORC2底物P-AKT（S473）达到50%的抑制[1]。MTI-31（0.1µmol/L）和RAD001（0.1µmol/L）联合处理786-O细胞6小时可显著抑制786-O细胞的增殖和侵袭，并上调LC3的表达，激活自噬通路[4]。
在体内，口服15mg/kg MTI-31和7.5mg/kg MRTX849 7天可显著抑制KRAS突变小鼠肺原位异种移植瘤模型的肿瘤生长，减少肿瘤血管生成和胶原沉积[5]。在KRAS肺癌小鼠模型中，每天口服10、20和40mg/kg的MTI-31在35天内产生剂量依赖性的肿瘤抑制，并强烈抑制mTOR生物标志物的表达[3]。
| Kinase experiment [1]: | |
Preparation Method | mTOR binding constant (Kd) of MTI-31 and binding assays for a panel of 98 protein kinases with MTI-31 at a fixed 1000nmol/L were performed by KINOMEscan™ Profiling Service for 6h. mTOR substrate phosphorylation assay was performed using recombinant mTOR enzyme, 50nmol/L unphosphorylated 4EBP1 and 100μmol/L ATP, detected using the LANCE® TR-FRET platform. IC50 values were generated using Graphpad PRISM 5 software. |
Reaction Conditions | 1000nmol/L; 6h |
Applications | MTI-31 binds strongly and specifically to mTOR and weakly to the remaining kinases tested. |
| Cell experiment [2]: | |
Cell lines | HCC827 cells |
Preparation Method | Standard cell culture methods and reagents were used to culture HCC827 cells. The cell cultures underwent regular testing to ensure they remained free of mycoplasma contamination. Use G418 selection to create a stable population of Luciferase-tagged H1975 cells. Package different pGIPZ/pTRIPZ-shRNA viruses in the 293T cells prior to infecting cancer cells. The gene-depletion process with pTRIPZ was activated by adding 1μg/mL doxycycline (Dox) for a period of 5 to 7 days. Cells were plated at 5% to 10% confluence in a 96-well plate and treated with MTI-31 (0.01, 0.1 and 1.0μmol/L) for three days before cell proliferation was assessed using MTS reagent. Evaluate pGIPZ-ShRNA-expressing cells' viability and growth through quantifying GFP-positive cells resistant to puromycin. |
Reaction Conditions | 0.01, 0.1 and 1.0μmol/L; 0, 24, 48 and 72 hours |
Applications | MTI-31 significantly inhibited the proliferation of all HCC827 cell lines with an IC50 value of 0.247 ± 0.03μmol/L. |
| Animal experiment [3]: | |
Animal models | Female Balb/c nude mice |
Preparation Method | Create the KRAS mutant lung orthotopic transplantation tumor model by injecting 1 × 106 luciferase labeled HCC44 cells suspended in 50μL PBS into the left lung of female Balb/c nude mice. The mice received an intraperitoneal injection of D-luciferin at a concentration of 150mg/kg for tumor staging which was followed by bioluminescence imaging 6 minutes after injection. The tumors underwent randomization into treatment groups based on fluorescence intensity after seven days post cell injection. MTI-31 was used as a single therapy or part of combination treatment at a dose of 15mg/kg administered orally. The progression of lung tumors was tracked through signals captured by bioluminescence imaging. Create H1792 xenografts by injecting 5 × 106 H1792 cells subcutaneously into the right flank of nude mice. Assign mice to different treatment groups (n=7) after tumor growth reached roughly 150mm3. Tumor volume was calculated as the formula: length × width2 × 0.5. The whole experimental period lasted 35 days. |
Dosage form | 15 mg/kg/day for 35 days; p.o. |
Applications | MTI-31 treatment significantly reduced tumor growth, resulting in a decrease in the number of Ki67+ proliferating cells and an increase in the number of apoptotic cells. |
References: | |
| Cas No. | 1567915-38-1 | SDF | Download SDF |
| 别名 | LXI-15029 | ||
| 分子式 | C26H30N6O3 | 分子量 | 474.55 |
| 溶解度 | DMSO : 8.33 mg/mL (17.55 mM; ultrasonic and warming and heat to 60°C) | 储存条件 | Store at -20°C |
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1 mg | 5 mg | 10 mg |
| 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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动物平均体重 | g | |
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动物数量 | 只 |
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2.
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