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]。