AP26113 is a highly potent ALK inhibitor with IC50 of 0.62 nM. As an ALK inhibitor, AP26113 overcomes mutation-based resistance in NSCLC models. Multiple mutations in ALK were identified that conferred resistance to crizotinib, but not AP26113, including the L1196M "gatekeeper" mutation which has now been observed clinically in patients who initially responded to crizotinib and then relapsed. AP26113 also inhibits activated EGFR in preclinical models, including the T790M "gatekeeper" mutant that confers resistance to current EGFR inhibitors. Constitutive EGFR activity due to activating mutation is a key feature of certain non-small cell lung cancers, and the T790M mutation causes resistance to inhibitor therapy in approximately 50 percent of these cases. In preclinical studies, AP26113 was shown to be specific for mutated EGFR and avoids inhibition of native (endogenous or unmutated) EGFR; such inhibition is thought to be associated with the toxicity of other EGFR inhibitors.
|Source||Mol Cancer Res (2015). Figure 1. AP26113|
|Cell Lines||KARPAS-299, SUP-M2 cell lines|
|Concentrations||0, 100, 300, and 1000 nmol/L|
|Incubation Time||20 nmol/L|
|Results||In all AP26113-resistant KARPAS-derived cell lines, STAT-3 P-Tyr705 was present at higher drug doses than the one observed for parental cells and correlated with the persistent NPM-ALK phosphorylation|
|Cell lines||H3122, H3122 CR, A549, H1299, SKBR3, H522, H460, and BT474 cells|
|Preparation method||Survival assays
For 72-h drug treatments, 3000 cells were plated in replicates of six into 96-well plates. Following drug treatments, cells were incubated with CellTiter-Glo assay reagent (Promega) for 10 min and luminescence was measured using a Centro LB 960 microplate luminometer (Berthold Technologies).
|Incubation time||72 h|
|Animal models||H3122 CR xenografts in athymic nude mice|
|Dosages||50 mg/kg/day for 17 days|
|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.
Abstract 1794: AP26113 is a dual ALK/EGFR inhibitor: Characterization against EGFR T790M in cell and mouse models of NSCLC.
Victor et al. Cancer Research. 2012 April 15;Volume 72, Issue 8, Supplement 1.
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Brigatinib (AP26113) is a potent and selective ALK (IC50, 0.6 nM) and ROS1 (IC50, 0.9 nM) inhibitor. It also inhibits ROS1, FLT3, and mutant variants of FLT3 (D835Y) and EGFR with lower potentcy.
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