Ensartinib (dihydrochloride)

Ensartinib dihydrochloride (X-396 dihydrochloride) is a potent and dual ALK/MET inhibitor with IC₅₀s of <0.4 nM and 0.74 nM, respectively. IC50 & Target: IC50: <0.4 nM (ALK), 0.74 nM (MET)^[1] In Vitro: Ensartinib (X-396) dihydrochloride is a potent and dual ALK/MET inhibitor with IC₅₀s of <0.4 nM and 0.74 nM, respectively. Ensartinib dihydrochloride is potent in H3122 lung cancer cells harboring EML4-ALK E13;A20 (IC₅₀: 15 nM). Ensartinib dihydrochloride is also potent in H2228 lung cancer cells harboring EML4-ALK E6a/b; A20 (IC₅₀: 45 nM). Furthermore, X-376 is potent in SUDHL-1 lymphoma cells harboring NPM-ALK (IC₅₀: 9 nM)^[1]. In Vivo: Ensartinib (X-396) dihydrochloride shows substantial bioavailability and moderate half-lives in vivo. Nude mice harboring H3122 xenografts are treated with Ensartinib dihydrochloride at 25 mg/kg bid. Ensartinib dihydrochloride significantly delays the growth of tumors compared to vehicle alone. In the xenograft experiments, Ensartinib dihydrochloride appears well-tolerated in vivo. Mouse weight is unaffected by Ensartinib dihydrochloride treatment. Drug-treated mice appear healthy and do not display any signs of compound related toxicity. To further assess potential side effects of Ensartinib dihydrochloride, additional systemic toxicity and toxico-kinetic studies are performed in Sprague Dawley (SD) rats. Following 10 days of repeated oral administration of Ensartinib dihydrochloride at 20, 40, 80 mg/kg in SD rats, all animals survive to study termination. The no significant toxicity (NST) levels are determined to be 80 mg/kg for Ensartinib dihydrochloride. At NST levels, Ensartinib dihydrochloride achieves an AUC of 66 μM×hr and a C_max of 7.19 μM^[1].