Ceritinib dihydrochloride

Ceritinib (LDK378) dihydrochloride is a selective, orally bioavailable and ATP-competitive ALK tyrosine kinase inhibitor with an IC₅₀ of 200 pM. Ceritinib dihydrochloride also inhibits IGF-1R, InsR, and STK22D with IC₅₀ values of 8, 7, and 23 nM, respectively. Ceritinib dihydrochloride shows great antitumor potency^[1][2]. IC50 & Target:IC50: 0.2 nM (ALK), 8 nM (IGF-1R), 7 nM (InsR), 23 nM (STK22D)^[1] In Vitro:Ceritinib dihydrochloride shows great anti-proliferative activity in Ba/F3-NPM-ALK and Karpas290 cells with IC₅₀ of 26.0 nM and 22.8 nM, compared with IC₅₀ of 319.5 nM and 2477 nM in Ba/F3-Tel-InsR and Ba/F3-WT cells^[1]. In Vivo:Ceritinib dihydrochloride is designed to reduce the possibility of forming reactive metabolites and shows undetectable levels of glutathione (GSH) adducts (<1%) in liver microsomes. Ceritinib (LDK378) has relatively good metabolic stability, with moderate CYP3A4 (Midazolam substrate) inhibition and hERG inhibition. Ceritinib dihydrochloride exhibits low plasma clearance in animals (mouse, rat, dog and monkey) compared to liver blood flow, with the oral bioavailability of above 55% in mouse, rat, dog and monkey. Ceritinib dihydrochloride induces a dose-dependent growth inhibition and tumor regression in the Karpas299 and H2228 rat xenograft models, with no body-weight loss. Ceritinib (LDK378) shows no impact on insulin levels or plasma glucose utilization in the mouse upon chronic dosing up to 100 mg/kg^[1].