恩沙替尼

中文名称:

恩沙替尼

中文同义词:

恩沙替尼;恩沙替尼(X-376);ALK抑制剂(ENSARTINIB);恩沙替尼(X 396)

英文名称:

X-376

英文同义词:

X-376;X-396;6-Amino-5-[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-N-[4-[(4-methyl-1-piperazinyl)carbonyl]phenyl]-3-pyridazinecarboxamide;Ensartinib;(R)-6-amino-5-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-N-(4-(4-methylpiperazine-1-carbonyl)phenyl)pyridazine-3-carboxamide;6-amino-5-[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-N-[4-(4-methylpiperazine-1-carbonyl)phenyl]pyridazine-3-carboxamide;CS-1720;3-Pyridazinecarboxamide, 6-amino-5-[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-N-[4-[(4-methyl-1-piperazinyl)carbonyl]phenyl]-

CAS号:

1365267-27-1

分子式:

C25H25Cl2FN6O3

分子量:

547.41

EINECS号:

相关类别:

抑制剂;小分子抑制剂;科研试剂;细胞生物学试剂;成熟工艺

Mol文件:

1365267-27-1.mol

沸点 

695.1±55.0 °C(Predicted)

密度 

1.428±0.06 g/cm3(Predicted)

酸度系数(pKa)

10.70±0.70(Predicted)

二代ALK抑制剂

二代ALK抑制剂恩沙替尼（X-396）全面优于第一代克唑替尼，2016年6月开始全球多中心3期临床，2017年6月获批多中心国内3期临床批件，均为一线用药，预计2019~2021年将上市销售。预计全球销售额5亿美元级别，其中海外3亿美元，国内12亿元。此外，X-396还于2017年12月在美国启动“ALK阳性晚期恶性黑色素瘤”2期临床研究，是全球首个ALK抑制剂治疗黑色素瘤的临床研究，有望以“孤儿药”获批上市。市场空间8亿美元，以渗透率40%计算，销售峰值为3.2亿美元。总体销售峰值在50亿元左右。

市场情况

恩沙替尼处于一线治疗 III 期临床，疗效有望看齐艾乐替尼，将和艾乐替尼、 Brigatinib 共同竞争国际市场；恩沙替尼有望复制埃克替尼的成功。 恩沙替尼国内有望以优异的 II 期临床数据直接申请上市，复制埃克替尼的成功，国内峰值销售有望超过 20 亿元。

生物活性

X-376是ALK抑制剂，对治疗非小细胞性肺癌有潜在疗效。

靶点

Target Value ALK ()

Target

Value

ALK ()

体外研究

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 (IC 50 : 77 nM). X-376 is also potent in H2228 lung cancer cells harboring EML4-ALK E6a/b; A20 (IC 50 : 57 nM). Furthermore, X-376 is potent in SUDHL-1 lymphoma cells harboring NPM-ALK (IC 50 : 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 IC 50 s of 142 nM, 150 nM, 15.137 μM and 3.062 μM, respectively.

体内研究

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/kg for X-376. At NST levels, X-376 achieves an AUC of 41 μM×hr and a C max of 5.04 μM.