Department of Clinical Research, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, 610041, China.
Department of Breast Center, West China Hospital, Sichuan University, Chengdu, 610041, China.
Eur J Med Chem. 2024 Oct 5;276:116702. doi: 10.1016/j.ejmech.2024.116702. Epub 2024 Jul 23.
Human epidermal growth factor receptor 2 (HER2) is a transmembrane receptor-like protein with tyrosine kinase activity that plays a vital role in processes such as cell proliferation, differentiation, and angiogenesis. The degree of malignancy of different cancers, notably breast cancer, is strongly associated with HER2 amplification, overexpression, and mutation. Currently, widely used clinical HER2 tyrosine kinase inhibitors (TKIs), such as lapatinib and neratinib, have several drawbacks, including susceptibility to drug resistance caused by HER2 mutations and adverse effects from insufficient HER2 selectivity. To address these issues, it is essential to create innovative HER2 TKIs with enhanced safety, effectiveness against mutations, and high selectivity. Typically, SPH5030 has advanced to phase I clinical trials for its strong suppression of four HER2 mutations. This review discusses the latest research progress in HER2 TKIs, with a focus on the structural optimization process and structure-activity relationship analysis. In particular, this study highlights promising design strategies to address these challenges, providing insightful information and inspiration for future development in this field.
人类表皮生长因子受体 2（HER2）是一种具有酪氨酸激酶活性的跨膜受体样蛋白，在细胞增殖、分化和血管生成等过程中发挥着重要作用。不同癌症（尤其是乳腺癌）的恶性程度与 HER2 扩增、过表达和突变密切相关。目前，广泛应用于临床的 HER2 酪氨酸激酶抑制剂（TKIs），如拉帕替尼和奈拉替尼，存在一些缺点，包括由 HER2 突变引起的药物耐药性和 HER2 选择性不足的不良反应。为了解决这些问题，必须开发具有增强安全性、针对突变的有效性和高选择性的创新型 HER2 TKIs。通常情况下，SPH5030 因其对四种 HER2 突变的强烈抑制作用，已进入 I 期临床试验。本综述讨论了 HER2 TKIs 的最新研究进展，重点介绍了结构优化过程和构效关系分析。特别是，本研究强调了有前途的设计策略，以解决这些挑战，为该领域的未来发展提供了有见地的信息和灵感。
