Naquotinib

Naquotinib (ASP8273) 是有口服活性,不可逆的 EGFR 突变体抑制剂；对EGFR突变体和EGFR的 IC50 值分别为8-33和230 nM。

研究领域 >> 癌症

EGFR:230 nM (IC50)

EGFRT790M

EGFRL858R/T790M

EGFRL858R

EGFRExon 19 deletion/T790M

在使用内源性EGFR依赖性细胞的测定中,Naquotinib抑制PC-9(del ex19),HCC827(del ex19),NCI-H1975(del ex19/T790M)和PC-9ER(del ex19/T790M)的生长,IC50为8-33 nM [1]。 Naquotinib在HCC827和NCI-H1975中选择性抑制EGFR及其下游信号通路ERn和Akt的磷酸化,而仅在1000nM时检测到抑制作用。在NCI-H1650(del ex19)中,Naquotinib抑制细胞生长。 IC50值为70nM,而其他EGFR-TKI仅部分有效[2]。

口服Naquotinib治疗剂量依赖性地诱导NCI-H1975(L858R/T790M),HCC827(del ex19)和PC-9(del ex19)异种移植模型中的肿瘤消退。给药方案不影响Naquotinib的疗效。在NCI-H1975异种移植模型中,在Naquotinib处理14天后实现肿瘤的完全消退。停止Naquotinib治疗后超过85天,50％的小鼠完全消退[2]。

[1]. Sakagami H, et al. ASP8273, a novel mutant-selective irreversible EGFR inhibitor, inhibits growth of non-small cell lung cancer (NSCLC) cells with EGFR activating and T790M resistance mutations. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1728. doi:10.1158/1538-7445.AM2014-1728

[2]. Konagai S, et al. ASP8273 selectively inhibits mutant EGFR signal pathway and induces tumor shrinkage in EGFR mutated tumor models. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2586. doi:10.1158/1538-7445.AM2015-2586

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