Tropomyosin receptor kinase (TRK) inhibition is an effective therapeutic approach for treatment of a variety of cancers. Despite the use of first-generation TRK inhibitor (TRKI) larotrectinib (1) resulting in significant therapeutic response in patients, acquired resistance develops invariably. The emergence of secondary mutations occurring at the solvent-front, xDFG, and gatekeeper regions of TRK represents a common mechanism for acquired resistance. However, xDFG mutations remain insensitive to second-generation macrocyclic TRKIs selitrectinib (3) and repotrectinib (4) designed to overcome the resistance mediated by solvent-front and gatekeeper mutations. Here, we report the structure-based drug design and discovery of a next-generation TRKI. The structure–activity relationship studies culminated in the identification of a promising drug candidate 8 that showed excellent in vitro potency on a panel of TRK mutants, especially TRKA^G667C in the xDFG motif, and improved in vivo efficacy than 1 and 3 in TRK wild-type and mutant fusion-driven tumor xenograft models, respectively.

中文翻译：

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发现用于对抗与蛋白质突变相关的多重耐药性的下一代原肌球蛋白受体激酶抑制剂

原肌球蛋白受体激酶 (TRK) 抑制是治疗多种癌症的有效治疗方法。尽管使用第一代 TRK 抑制剂 (TRKI) larotrectinib ( 1 ) 在患者中产生显着的治疗反应，但总是会产生获得性耐药性。发生在 TRK 的溶剂前沿、xDFG 和看门人区域的次级突变的出现代表了获得性抗性的常见机制。然而，xDFG 突变对第二代大环 TRKIs selitrectinib ( 3 ) 和 repotrectinib ( 4 )仍然不敏感) 旨在克服由溶剂前沿和看门人突变介导的抗性。在这里，我们报告了基于结构的药物设计和下一代 TRKI 的发现。构效关系研究最终确定了一种有前途的候选药物8，该候选药物在一组 TRK 突变体中显示出优异的体外效力，尤其是xDFG 基序中的TRKA ^G667C，并且在 TRK 野生型中比1和3提高了体内功效。类型和突变融合驱动的肿瘤异种移植模型，分别。