X-396 is a potent and highly specific ALK small molecule tyrosine kinase inhibitors (TKIs). In Ambit kinome screens, cell growth inhibition studies, and surrogate kinase assays,X-396 was more potent inhibitors of ALK but less potent inhibitors of MET compared to PF-02341066. X-396 displayed potent antitumor activity in vivo with favorable pharmacokinetic and toxicity profiles.
Science. 2017 Dec 1;358(6367).
The target landscape of clinical kinase drugs
Ensartinib purchased from AbMole
|Source||Munich Industrial University (2018). Figure 36. X-396 (AbMole BioScience)|
|Method||Kinase binding of small molecule inhibitors|
|Cell Lines||BT-474 cells, Caki-1 cells, KM-12 and HEK-293 cells|
|Incubation Time||24 h|
|Results||Notably, the photosensitizing effect of small molecule inhibitors can also be used for photodynamic therapy of cancer.|
|Source||Science (2017). Figure 4. X-396 (Abmole Bioscience)|
|Method||Cell viability and proliferation assays|
|Cell Lines||A-431 and ACHN cells|
|Incubation Time||72 h|
|Results||Regardless of whether or not EGFR carried an activating mutation, the combination was always more effective in inhibiting cell viability and proliferation than any one drug alone.|
|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.
Insights into ALK-driven cancers revealed through development of novel ALK tyrosine kinase inhibitors.
Lovly CM et al. Cancer Res. 2011 Jul 15;71(14):4920-31. PMID: 21613408.
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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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