INK128 (also known as MLN0128, Sapanisertib) is also an orally bioavailable mTOR inhibitor of raptor-mTOR (TOR complex 1 or TORC1) and rictor-mTOR (TOR complex 2 or TORC2) with potential antineoplastic activity. INK128 blocks the phosphorylation of downstream substrates of both TORC1 and TORC2. INK128 (MLN0128) exhibits an enzymatic inhibition activity against mTOR and more than 100-fold selectivity to PI3K kinases. INK128 interferes with the growth of cell lines which are resistant to rapamycin and pan-PI3K inhibitors. Oral administration of INK128 (MLN0128) inhibits angiogenesis and tumor growth in several xenograft models. In vitro and in vivo studies showed that p-4EBP1 and p-Akt inhibition could be predictive markers of TORC2 inhibition in MM cell lines. Dual TORC1/2 inhibition showed better inhibition of adhesion to BM microenvironmental cells and inhibition of homing in vivo.
Clin Cancer Res. 2018 Nov 15;24(22):5658-5672.
Increased Synthesis of MCL-1 Protein Underlies Initial Survival of EGFR-Mutant Lung Cancer to EGFR Inhibitors and Provides a Novel Drug Target.
INK128 (Sapanisertib) purchased from AbMole
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Source | Clinical Cancer Research (2018 Nov). Figure 2. MLN0128 (Abmole Bioscience) |
| Method | Western blotting | |
| Cell Lines | PC9, HCC4006 and HCC827 cells | |
| Concentrations | 200 nM | |
| Incubation Time | - | |
| Results | Consistently, MCL-1 levels were decreased in both AZD2014 and MLN0128-treated cells. |
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Source | Cancer Biology & Therapy (2015). Figure 1. INK-128 |
| Method | MTT assay | |
| Cell Lines | HT-29 cells | |
| Concentrations | 5, 25 and 100 nM | |
| Incubation Time | 72 h | |
| Results | INK-128 dose-dependently inhibited the number of survival colonies, while increasing the PtdIns staining in HT-29 cells. |
| Molecular Weight | 309.33 |
| Formula | C15H15N7O |
| CAS Number | 1224844-38-5 |
| Solubility (25°C) | DMSO 52 mg/mL |
| Storage |
Powder -20°C 3 years ; 4°C 2 years In solvent -80°C 6 months ; -20°C 1 month |
| Species | Mouse | Rat | Rabbit | Guinea pig | Hamster | Dog |
| Weight (kg) | 0.02 | 0.15 | 1.8 | 0.4 | 0.08 | 10 |
| Body Surface Area (m2) | 0.007 | 0.025 | 0.15 | 0.05 | 0.02 | 0.5 |
| Km factor | 3 | 6 | 12 | 8 | 5 | 20 |
| Animal A (mg/kg) = Animal B (mg/kg) multiplied by | Animal B Km |
| Animal A Km |
For example, to modify the dose of Compound A used for a mouse (20 mg/kg) to a dose based on the BSA for a rat, multiply 20 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for Compound A of 10 mg/kg.
[1] Maiso P, et al. Blood. Defining the role of TORC1/2 in multiple myeloma.
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