Precision oncology is premised on identifying and drugging proteins and pathways that drive tumorigenesis or are required for survival of tumor cells. Across diverse cancer types, the signaling pathway emanating from receptor tyrosine kinases on the cell surface to RAS and the MAP kinase pathway is the most frequent target of oncogenic mutations, and key proteins in this signaling axis including EGFR, SHP2, RAS, BRAF, and MEK have long been a focus in cancer drug discovery. In this review, we provide an overview of historical and recent efforts to develop inhibitors targeting these nodes with an emphasis on the role that an understanding of protein structure and regulation has played in inhibitor discovery and characterization. Beyond its well-established role in structure-based drug design, structural biology has revealed mechanisms of allosteric regulation, distinct effects of activating oncogenic mutations, and other vulnerabilities that have opened new avenues in precision cancer drug discovery.

中文翻译：

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癌症中 RTK/Ras/MAP 激酶通路靶向的结构视角


精准肿瘤学的前提是识别和药物治疗驱动肿瘤发生或肿瘤细胞生存所需的蛋白质和途径。在不同的癌症类型中，从细胞表面的受体酪氨酸激酶到 RAS 和 MAP 激酶途径的信号传导通路是致癌突变最常见的目标，该信号传导轴中的关键蛋白包括 EGFR、SHP2、RAS、BRAF 和MEK 长期以来一直是癌症药物发现的焦点。在这篇综述中，我们概述了开发针对这些节点的抑制剂的历史和最近的努力，重点是了解蛋白质结构和调节在抑制剂发现和表征中所发挥的作用。除了在基于结构的药物设计中的既定作用之外，结构生物学还揭示了变构调节机制、激活致癌突变的独特作用以及其他漏洞，这些漏洞为精准癌症药物发现开辟了新途径。