Drug Design and Development Research Center, The Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Sciences, Tehran, Iran.
Department of Medicinal Chemistry, School of Pharmacy, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran; Toxicology Research Center, Medical Basic Sciences Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
Eur J Med Chem. 2021 Oct 5;221:113523. doi: 10.1016/j.ejmech.2021.113523. Epub 2021 May 4.
Despite significant improvements of new treatment options, cancer continues to represent as one of the most common and fatal disease. The EGFR signaling pathway is considered as a significant approach in targeted therapy of cancers. Blocking the EGFR-driven pathway by inhibiting the intracellular tyrosine kinase domain of EGFR have shown considerable improvement in cancer therapy. In an effort to identify EGFR tyrosine kinase inhibitors (TKI), several small molecules especially pyrimidine containing derivatives have been designed by applying molecular simulation and evaluated the emergence of epigenetic mutation and resistance problems restricted the long-term effectiveness of such medication and explained the need for further investigations in this field. In recent years, the studies have been focused on genetic alterations on EGFR tyrosine kinase domain, which led to the design and synthesis of more selective and effective inhibitors. Herein, we give an overview of the importance and status of EGFR inhibitors in cancer therapy. In addition, we provide an update of the recent advances in design, discovery and development of novel pyrimidine containing compounds as promising selective EGFR TK inhibitors.
尽管新的治疗选择取得了重大进展，但癌症仍然是最常见和最致命的疾病之一。EGFR 信号通路被认为是癌症靶向治疗的重要方法。通过抑制 EGFR 的细胞内酪氨酸激酶结构域来阻断 EGFR 驱动的途径，已显示出在癌症治疗方面有相当大的改善。为了确定 EGFR 酪氨酸激酶抑制剂 (TKI)，人们应用分子模拟设计了几种小分子，特别是嘧啶类衍生物，并评估了表观遗传突变和耐药性问题的出现，这些问题限制了此类药物的长期疗效，并解释了在该领域进一步研究的必要性。近年来，研究集中在 EGFR 酪氨酸激酶结构域的遗传改变上，这导致了更具选择性和更有效的抑制剂的设计和合成。本文综述了 EGFR 抑制剂在癌症治疗中的重要性和现状。此外，我们还介绍了近年来在设计、发现和开发新型嘧啶类化合物作为有前途的选择性 EGFR TK 抑制剂方面的最新进展。
