X-376 是一种有效的高特异性 ALK 酪氨酸激酶抑制剂 (TKI) (IC₅₀=0.61 nM)。X-376 是 MET 的较低效抑制剂 (IC₅₀=0.69 nM)。X-376 具有有效的抗肿瘤活性。

X-376 is a potent and highly specific ALK tyrosine kinase inhibitor (TKI) (IC 50 =0.61 nM). X-376 is a less potent inhibitor of MET (IC 50 =0.69 nM). X-376 displays potent anti-tumor activity.

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ALK 0.61 nM (IC50)

The ability of X-376 to inhibit the growth of different cancer cell lines harboring ALK fusions or point mutations is tested. X-376 is potent in H3122 lung cancer cells harboring EML4-ALK E13;A20 (IC50: 77 nM). X-376 is also potent in H2228 lung cancer cells harboring EML4-ALK E6a/b; A20 (IC50: 57 nM). Furthermore, X-376 is potent in SUDHL-1 lymphoma cells harboring NPM-ALK (IC50: 32 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 IC50s of 142 nM, 150 nM, 15.137 μM and 3.062 μM, respectively. has not independently confirmed the accuracy of these methods. They are for reference only.

The effects of X-376 in vivo against H3122 xenografts are examined. A pharmacokinetic study reveals that X-376 shows substantial bioavailability and moderate half-lives in vivo. Nude mice harboring H3122 xenografts are treated with X-376 at 50 mg/kg bid. X-376 significantly delays the growth of tumors compared to vehicle alone. In the xenograft experiments, X-376 appears well-tolerated in vivo. Mouse weight is unaffected by X-376 treatment. Drug-treated mice appear healthy and do not display any signs of compound related toxicity. To further assess potential side effects of X-376, additional systemic toxicity and toxico-kinetic studies are performed in Sprague Dawley (SD) rats. Following 10 days of repeated oral administration of X-376 at 25, 50, 100 mg/kg in SD rats, all animals survive to study termination. The no significant toxicity (NST) levels are determined to be 50 mg/

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[1]. Lovly CM, et al. Insights into ALK-driven cancers revealed through development of novel ALK tyrosine kinaseinhibitors. Cancer Res. 2011 Jul 15;71(14):4920-31.

In Vitro: DMSO : 100 mg/mL (182.68 mM; Need ultrasonic)配制储备液