Since 2011, with the approval of crizotinib and subsequent approval of four additional targeted therapies, anaplastic lymphoma kinase (ALK) inhibitors have become important treatments for a subset of patients with lung cancer. Each generation of ALK inhibitor showed improvements in terms of central nervous system (CNS) penetration and potency against wild-type (WT) ALK, yet a key continued limitation is their susceptibility to resistance from ALK active-site mutations. The solvent front mutation (G1202R) and gatekeeper mutation (L1196M) are major resistance mechanisms to the first two generations of inhibitors while patients treated with the third-generation ALK inhibitor lorlatinib often experience progressive disease with multiple mutations on the same allele (mutations in cis , compound mutations). TPX-0131 is a compact macrocyclic molecule designed to fit within the ATP-binding boundary to inhibit ALK fusion proteins. In cellular assays, TPX-0131 was more potent than all five approved ALK inhibitors against WT ALK and many types of ALK resistance mutations, e.g., G1202R, L1196M, and compound mutations. In biochemical assays, TPX-0131 potently inhibited (IC50 <10 nmol/L) WT ALK and 26 ALK mutants (single and compound mutations). TPX-0131, but not lorlatinib, caused complete tumor regression in ALK (G1202R) and ALK compound mutation-dependent xenograft models. Following repeat oral administration of TPX-0131 to rats, brain levels of TPX-0131 were approximately 66% of those observed in plasma. Taken together, preclinical studies show that TPX-0131 is a CNS-penetrant, next-generation ALK inhibitor that has potency against WT ALK and a spectrum of acquired resistance mutations, especially the G1202R solvent front mutation and compound mutations, for which there are currently no effective therapies. This article is featured in Highlights of This Issue, [p. 1497][1] [1]: /lookup/volpage/20/1497?iss=9

中文翻译：

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TPX-0131，一种有效的 CNS 渗透剂、野生型 ALK 和 ALK 抗性突变的下一代抑制剂


自 2011 年以来，随着克唑替尼的批准以及随后另外四种靶向疗法的批准，间变性淋巴瘤激酶 (ALK) 抑制剂已成为部分肺癌患者的重要治疗方法。每一代 ALK 抑制剂在中枢神经系统 (CNS) 渗透性和针对野生型 (WT) ALK 的效力方面均表现出改善，但一个关键的持续限制是它们对 ALK 活性位点突变的耐药性的敏感性。溶剂前沿突变 (G1202R) 和看门突变 (L1196M) 是前两代抑制剂的主要耐药机制，而使用第三代 ALK 抑制剂 lorlatinib 治疗的患者经常会出现进展性疾病，且同一等位基因上存在多个突变（顺式突变）。 ，复合突变）。 TPX-0131 是一种紧凑的大环分子，旨在适应 ATP 结合边界以抑制 ALK 融合蛋白。在细胞测定中，TPX-0131 比所有五种已批准的 ALK 抑制剂更有效地对抗 WT ALK 和许多类型的 ALK 耐药突变，例如 G1202R、L1196M 和复合突变。在生化测定中，TPX-0131 有效抑制 (IC50 <10 nmol/L) WT ALK 和 26 ALK 突变体（单一和复合突变）。 TPX-0131（而非洛拉替尼）在 ALK (G1202R) 和 ALK 复合突变依赖性异种移植模型中引起肿瘤完全消退。大鼠重复口服 TPX-0131 后，TPX-0131 的脑水平约为血浆中观察到的水平的 66%。 总而言之，临床前研究表明，TPX-0131 是一种中枢神经系统渗透性的下一代 ALK 抑制剂，对 WT ALK 和一系列获得性耐药突变具有效力，特别是 G1202R 溶剂前沿突变和复合突变，目前有针对这些突变的研究。没有有效的治疗方法。本文收录于本期亮点，[p. 11]。 1497][1][1]：/lookup/volpage/20/1497？国际空间站=9