School of Pharmacy, Bandung Institute of Technology, Jalan Ganesha 10, Bandung 40132, Indonesia.
Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo 113-0033, Japan.
Molecules. 2022 Jan 26;27(3):819. doi: 10.3390/molecules27030819.
Lung cancer has a high prevalence, with a growing number of new cases and mortality every year. Furthermore, the survival rate of patients with non-small-cell lung carcinoma (NSCLC) is still quite low in the majority of cases. Despite the use of conventional therapy such as tyrosine kinase inhibitor for Epidermal Growth Factor Receptor (EGFR), which is highly expressed in most NSCLC cases, there was still no substantial improvement in patient survival. This is due to the drug's ineffectiveness and high rate of resistance among individuals with mutant EGFR. Therefore, the development of new inhibitors is urgently needed. Understanding the EGFR structure, including its kinase domain and other parts of the protein, and its activation mechanism can accelerate the discovery of novel compounds targeting this protein. This study described the structure of the extracellular, transmembrane, and intracellular domains of EGFR. This was carried out along with identifying the binding pose of commercially available inhibitors in the ATP-binding and allosteric sites, thereby clarifying the research gaps that can be filled. The binding mechanism of inhibitors that have been used clinically was also explained, thereby aiding the structure-based development of new drugs.
肺癌发病率高，每年新发病例和死亡人数不断增加。此外，大多数情况下，非小细胞肺癌（NSCLC）患者的生存率仍然相当低。尽管使用了常规疗法，如针对表皮生长因子受体（EGFR）的酪氨酸激酶抑制剂，因为 EGFR 在大多数 NSCLC 病例中高表达，但患者的生存并没有得到实质性的改善。这是由于药物在具有突变 EGFR 的个体中的无效性和高耐药率所致。因此，迫切需要开发新的抑制剂。了解 EGFR 的结构，包括其激酶结构域和蛋白质的其他部分，以及其激活机制，可以加速发现针对该蛋白的新型化合物。本研究描述了 EGFR 的细胞外、跨膜和细胞内结构域的结构。同时确定了 ATP 结合和变构位点中商业上可用抑制剂的结合构象，从而阐明了可以填补的研究空白。还解释了临床上使用的抑制剂的结合机制，从而有助于基于结构的新药开发。
