6-氨基-5-[(1R)-1-(2,6-二氯-3-氟苯基)乙氧基]-N-[4-[[(3R,5S)-3,5-二甲基-1-哌嗪基]羰基]苯基]-3-哒嗪甲酰胺

The ability of Ensartinib (X-396) to inhibit the growth of different cancer cell lines harboring ALK fusions or point mutations is tested. Ensartinib is potent in H3122 lung cancer cells harboring EML4-ALK E13;A20 (IC ₅₀ : 15nM). Ensartinib is also potent in H2228 lung cancer cells harboring EML4-ALK E6a/b; A20 (IC ₅₀ : 45 nM). Furthermore, X-376 is potent in SUDHL-1 lymphoma cells harboring NPM-ALK (IC ₅₀ : 9 nM). X-376 also inhibits SY5Y neuroblastoma cells harboring ALK F1174L, MKN-45 gastric carcinoma cells harboring MET dependent, HepG2 cells and PC-9 lung cancer cell lines harboring EGFR exon 19 del with IC ₅₀ s of 68 nM, 156 nM, 9.644 μM and 2.989 μM, respectively.

The effects of Ensartinib (X-396) in vivo against H3122 xenografts are examined. A pharmacokinetic study reveals that Ensartinib shows substantial bioavailability and moderate half-lives in vivo. Nude mice harboring H3122 xenografts are treated with Ensartinib at 25mg/kg bid. Ensartinib significantly delays the growth of tumors compared to vehicle alone. In the xenograft experiments, Ensartinib appears well-tolerated in vivo. Mouse weight is unaffected by Ensartinib treatment. Drug-treated mice appear healthy and do not display any signs of compound related toxicity. To further assess potential side effects of Ensartinib, additional systemic toxicity and toxico-kinetic studies are performed in Sprague Dawley (SD) rats. Following 10 days of repeated oral administration of Ensartinib 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 80mg/kg for Ensartinib. At NST levels, Ensartinib achieves an AUC of 66 μM×hr and a C _max of 7.19 μM.