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0131是哪里的区号,TPX-0131, a Potent CNS-penetrant, Next-generation Inhibitor of Wild-type ALK and ALK

发布日期:2021-11-28 04:26:39 作者: 点击:
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

中文翻译:

TPX-0131,一种有效的 CNS 渗透剂,下一代野生型 ALK 和 ALK 抗性突变抑制剂

自 2011 年以来,随着克唑替尼的获批以及随后四种其他靶向疗法的获批,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) 渗透和对野生型 (WT) ALK 的效力方面都表现出改善,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)和看门人突变(L1196M)是前两代抑制剂的主要耐药机制,而接受第三代 ALK 抑制剂劳拉替尼治疗的患者通常会出现进展性疾病,同一等位基因上有多个突变(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。在细胞分析中,TPX-0131 比所有五种批准的 ALK 抑制剂更有效地对抗 WT ALK 和许多类型的 ALK 抗性突变,例如 G1202R、L1196M 和复合突变。在生化分析中,TPX-0131 有效抑制 (IC50