CH5424802, a Selective ALK Inhibitor Capable of Blocking the Resistant Gatekeeper Mutant
CH5424802, a Selective ALK Inhibitor Capable of Blocking the Resistant Gatekeeper Mutant
复制标题
DOI：
10.1016/j.ccr.2011.04.004
复制
发表时间：
2011-05-17
期刊：
影响因子：
50.3
通讯作者：
Aoki, Yuko
中科院分区：
文献类型：
--
作者：
Sakamoto, Hiroshi;Tsukaguchi, Toshiyuki;Aoki, Yuko
间变性淋巴瘤激酶（ALK）是一种酪氨酸激酶，在某些癌症中，随着基因改变（如染色体易位、扩增或点突变）而组成性激活。在此，我们鉴定了CH 5424802，一种具有独特化学支架的强效、选择性和口服ALK抑制剂，在体外和体内对ALK基因改变的癌症（如表达EML 4-ALK融合的非小细胞肺癌（NSCLC）细胞和表达NPM-ALK融合的间变性大细胞淋巴瘤（ALCL）细胞）显示出优先抗肿瘤活性。CH 5424802抑制ALK L1196 M（对应于赋予激酶抑制剂常见耐药性的看门突变），并阻断EML 4-ALK L1196 M驱动的细胞生长。我们的结果支持CH 5424802治疗ALK驱动肿瘤患者的临床评价潜力。
Anaplastic lymphoma kinase (ALK) is a tyrosine kinase that is constitutively activated in certain cancers, following gene alterations such as chromosomal translocation, amplification, or point mutation. Here, we identified CH5424802, a potent, selective, and orally available ALK inhibitor with a unique chemical scaffold, showing preferential antitumor activity against cancers with gene alterations of ALK, such as nonsnnall cell lung cancer (NSCLC) cells expressing EML4-ALK fusion and anaplastic large-cell lymphoma (ALCL) cells expressing NPM-ALK fusion in vitro and in vivo. CH5424802 inhibited ALK L1196M, which corresponds to the gatekeeper mutation conferring common resistance to kinase inhibitors, and blocked EML4-ALK L1196M-driven cell growth. Our results support the potential for clinical evaluation of CH5424802 for the treatment of patients with ALK-driven tumors.