摘要

KIT is a type-3 receptor tyrosine kinase that is frequently mutated at exon 11 or 17 in a variety of cancers. First-generation KIT tyrosine kinase inhibitors (TKI) are ineffective against KIT exon 17 mutations, which favor an active conformation that prevents these TKIs from binding. The ATP-competitive inhibitors, midostaurin and avapritinib, which target the active kinase conformation, were developed to inhibit exon 17-mutant KIT. Because secondary kinase domain mutations are a common mechanism of TKI resistance and guide ensuing TKI design, we sought to define problematic KIT kinase domain mutations for these emerging therapeutics. Midostaurin and avapritinib displayed different vulnerabilities to secondary kinase domain substitutions, with the T670I gatekeeper mutation being selectively problematic for avapritinib. Although gatekeeper mutations often directly disrupt inhibitor binding, we provide evidence that T670I confers avapritinib resistance indirectly by inducing distant conformational changes in the phosphate-binding loop. These findings suggest combining midostaurin and avapritinib may forestall acquired resistance mediated by secondary kinase domain mutations. SIGNIFICANCE: This study identifies potential problematic kinase domain mutations for next-generation KIT inhibitors midostaurin and avapritinib.

译文

KIT 是一种 3 型受体酪氨酸激酶,在多种癌症中经常在第 11 或 17 号基因突变。第一代 KIT 酪氨酸激酶抑制剂 (TKI) 对 KIT exon 17 突变无效,有利于阻止这些 TKIs 结合的活性构象。针对活性激酶构象的 ATP 竞争性抑制剂米多汀和阿瓦普利替尼被开发出来以抑制 exon 17 突变试剂盒。因为次级激酶结构域突变是 TKI 抗性的常见机制,并指导随后的 TKI 设计,我们试图为这些新兴疗法定义有问题的 KIT 激酶结构域突变。Mido 'in 和 avapritinib 对次级激酶结构域替换表现出不同的脆弱性,T670I 看门人突变对 avapritinib 有选择性的问题。尽管看门人突变通常会直接破坏抑制剂结合,但我们提供的证据表明,T670I 通过诱导磷酸盐结合环的远处构象变化间接赋予阿瓦布里替尼抗性。这些发现表明,结合米多汀和阿瓦替尼可能阻止由次级激酶结构域突变介导的获得性耐药。意义: 本研究确定了下一代 KIT 抑制剂 mido 'in 和 avapritinib 的潜在问题激酶结构域突变。

Midostaurin

肿瘤 白血病 药物
概述  :  

2017年4月28日,美国食品药品管理局(FDA)批准了米哚妥林上市,用于治疗FLT3+的急性髓系白血病(AML)。米哚妥林是由瑞士诺华生产的,是25年来AML首款新药,也是第一款与化疗联用治疗AML的靶向药物。米哚妥林是多种激酶抑制剂,能抑制包括FLT3、PKC、C-FOS、MAPK、PDGFR、CDK1、KIT、VEGF等多种激酶活性。   国际多中心FLT3+ AML 3期临床试验中,研究人员检测了3277例AML,招募了其中符合要求的717例FLT3+患者,并将他们随机

Midostaurin 

释    义   n. 米哚妥林

例    句   The natural history of FLT3-mutated AML is changing after the approval of midostaurin for frontline therapy and gilteritinib for relapsed or refractory patients. 在米哚妥林和吉特替尼被批准用于一线治疗和复发或难治性患者后,FLT3突变的AML的自然史正在改变。

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