 Chemical Structure.png)
Physicochemical Properties
| Molecular Formula | C26H30N6O3 |
| Molecular Weight | 474.554805278778 |
| Exact Mass | 474.237 |
| CAS # | 1567915-38-1 |
| PubChem CID | 118591386 |
| Appearance | White to yellow solid powder |
| LogP | 3 |
| Hydrogen Bond Donor Count | 1 |
| Hydrogen Bond Acceptor Count | 8 |
| Rotatable Bond Count | 4 |
| Heavy Atom Count | 35 |
| Complexity | 745 |
| Defined Atom Stereocenter Count | 1 |
| SMILES | O1CC2CCC(C1)N2C1C2C=CC(C3C=CC=C(C(NC)=O)C=3)=NC=2N=C(N2CCOC[C@@H]2C)N=1 |
| InChi Key | LVPBYQVQBZLDAU-DZIBYMRMSA-N |
| InChi Code | InChI=1S/C26H30N6O3/c1-16-13-34-11-10-31(16)26-29-23-21(24(30-26)32-19-6-7-20(32)15-35-14-19)8-9-22(28-23)17-4-3-5-18(12-17)25(33)27-2/h3-5,8-9,12,16,19-20H,6-7,10-11,13-15H2,1-2H3,(H,27,33)/t16-,19?,20?/m0/s1 |
| Chemical Name | N-methyl-3-[2-[(3S)-3-methylmorpholin-4-yl]-4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)pyrido[2,3-d]pyrimidin-7-yl]benzamide |
| HS Tariff Code | 2934.99.9001 |
| Storage |
Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition | Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs) |
Biological Activity
| Targets | mTOR 0.2 nM (Ki) mTOR 39 nM (IC50, 100 μM ATP) mTORC1 mTORC2 |
| ln Vitro | MTI-31 targets both mTORC1 and mTORC2 activities in cancer cells by acting as a strong and specific inhibitor of mTOR enzymatic activity[1]. MTI-31 (0.01-100 μM) inhibits cell growth more strongly and significantly than Rapamycin[1]. The mTORC1 substrates P-S6K1(T389), P-S6(S235/6), P-4EBP1(T70), and the mTORC2 substrate P-AKT(S473) show dose-dependent inhibition upon 6 hours of treatment with MTI-31. In three representative tumor cell lines harboring mTOR pathway dysregulation (786-O renal, U87MG glioma, and MDA-MB-453 breast)], 50% inhibition was achieved at ≤0.12 μM. Bim- and GSK3 activity must be mTORC2-regulated for MTI-31-induced apoptosis to occur[1]. |
| ln Vivo | MTI-31 exhibits substantial anticancer efficaciousness and is a potent mTOR inhibitor in vivo. MTI-31 (5–40 mg/kg; oral) is effective in a number of tumor models that have PTEN deficit and/or HER2+/PIK3CAmut, as demonstrated by MDA-MB-453 and 786-O[1]. MTI-31 given orally to tumor-bearing nude mice suppresses the growth of H1975 tumors (25 mg/kg/d; oral) and U87MG tumors (30 mg/kg/d; oral)[2]. |
| Cell Assay |
Cell Proliferation Assay[1] Cell Types: MDA-MB-453 cells Tested Concentrations: 0.01, 0.1, 1, 10, 100 μM Incubation Duration: 3 days Experimental Results: Dramatically inhibited cellular proliferation after treatment for 3 days. Western Blot Analysis[1] Cell Types: 786-O renal, U87MG glioma and MDA-MB-453 breast cells Tested Concentrations: 0.12, 0.37, 1.11, 3.33, 10 μM Incubation Duration: 6 hrs (hours) Experimental Results: 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). |
| Animal Protocol |
Animal/Disease Models: Female nude mice bearing tumors of MDA-MB-453, 786-O or HCC1806[1] Doses: 2.5, 5, 10, 20, 40 mg/kg for MDA-MB-453 and 786- O; 20 and 40 mg/kg for HCC1806 Route of Administration: Treated orally via a one time/day (qd) regimen Experimental Results: 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. |
| References |
[1]. A Novel mTORC1/2 Inhibitor (MTI-31) Inhibits Tumor Growth, Epithelial-Mesenchymal Transition, Metastases, and Improves Antitumor Immunity in Preclinical Models of Lung Cancer. Clin Cancer Res. 2019 Jun 15;25(12):3630-3642. [2]. Molecular regulation of apoptotic machinery and lipid metabolism by mTORC1/mTORC2 dual inhibitors in preclinical models of HER2+/PIK3CAmut breast cancer. Oncotarget. 2016 Oct 11;7(41):67071-67086. [3]. Non-immunogenic, low-toxicity and effective glioma targeting MTI-31 liposomes . J Control Release. 2019 Dec 28;316:381-392. |
| Additional Infomation | mTORC 1/2 Inhibitor LXI-15029 is an orally bioavailable inhibitor of raptor-mammalian target of rapamycin (mTOR) complex 1 (mTOR complex 1; mTORC1) and rictor-mTOR complex 2 (mTOR complex 2; mTORC2), with potential antineoplastic activity. Upon oral administration, mTORC1/2 inhibitor LXI-15029 binds to the kinase domain of mTOR and inhibits both mTORC1 and mTORC2, in an ATP-competitive manner. This inhibits mTOR-mediated signaling and leads to both an induction of apoptosis and a decrease in the proliferation of mTORC1/2-expressing tumor cells. mTOR is a serine/threonine kinase that is upregulated in certain tumor cell types. It plays an important role in the PI3K/Akt/mTOR signaling pathway, which is often deregulated in cancer cells and promotes cell growth, survival, and resistance to chemotherapy and radiotherapy. |
Solubility Data
| Solubility (In Vitro) | DMSO: 8.33 mg/mL (17.55 mM) |
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 0.83 mg/mL (1.75 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 8.3 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 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 |