INK128 (also known as MLN0128) 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 (MLN0128) purchased from AbMole
|Source||Clinical Cancer Research (2018 Nov). Figure 2. MLN0128 (Abmole Bioscience)|
|Cell Lines||PC9, HCC4006 and HCC827 cells|
|Results||Consistently, MCL-1 levels were decreased in both AZD2014 and MLN0128-treated cells.|
|Source||Cancer Biology & Therapy (2015). Figure 1. INK-128|
|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.|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 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 resveratrol of 11.2 mg/kg.
|Solubility||DMSO 60 mg/mL|
Defining the role of TORC1/2 in multiple myeloma.
Maiso P, et al. Blood. 2011 Dec 22;118(26):6860-70. PMID: 22045983.
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