Faculty of Chemistry and Chemical Biology , TU Dortmund University , Otto-Hahn-Strasse 4a , 44227 Dortmund , ( Germany ).
Drug Discovery Hub Dortmund (DDHD) am Zentrum für Integrierte Wirkstoffforschung (ZIW) , TU Dortmund University , 44227 Dortmund ( Germany ).
J Med Chem. 2020 Jan 9;63(1):40-51. doi: 10.1021/acs.jmedchem.9b00964. Epub 2019 Aug 28.
The ErbB receptor tyrosine kinase family members EGFR (epidermal growth factor receptor) and Her2 are among the prominent mutated oncogenic drivers of non-small cell lung cancer (NSCLC). Their importance in proliferation, apoptosis, and cell death ultimately renders them hot targets in cancer therapy. Small-molecule tyrosine kinase inhibitors seem well suited to be tailor-made therapeutics for EGFR mutant NSCLC; however, drug resistance mutations limit their success. Against this background, the elucidation and visualization of the three-dimensional structure of cancer-related kinases provide valuable insights into their molecular functions. This field has undergone a revolution because X-ray crystal structure determinations aided structure-based drug design approaches and clarified the effect of activating and resistance-conferring mutations. Here, we present an overview of important mutations affecting EGFR and Her2 and highlight their influence on the kinase domain conformations and active site accessibility.
表皮生长因子受体（EGFR）和 Her2 是 ErbB 受体酪氨酸激酶家族成员，它们是导致非小细胞肺癌（NSCLC）的主要突变致癌驱动因子之一。它们在增殖、凋亡和细胞死亡中的重要作用使它们成为癌症治疗的热门靶点。小分子酪氨酸激酶抑制剂似乎非常适合作为 EGFR 突变 NSCLC 的定制治疗药物；然而，耐药性突变限制了它们的成功。在这种背景下，阐明和可视化与癌症相关的激酶的三维结构为它们的分子功能提供了有价值的见解。由于 X 射线晶体结构测定有助于基于结构的药物设计方法，并阐明了激活和耐药性赋予突变的影响，该领域发生了一场革命。在这里，我们概述了影响 EGFR 和 Her2 的重要突变，并强调了它们对激酶结构域构象和活性位点可及性的影响。
