Tumor Biology and Drug Discovery Laboratory, National Institute of Pathology, Indian Council of Medical Research, Safdarjang Hospital Campus, New Delhi 110029, India.
Research Institute for Science and Engineering (RISE), University of Sharjah, Sharjah P.O. Box 27272, United Arab Emirates.
Curr Pharm Des. 2023;29(44):3563-3578. doi: 10.2174/0113816128283615231218094706.
HER2 is the membrane receptor tyrosine kinase showing overexpression in several human malignancies, particularly breast cancer. HER2 overexpression causes the activation of Ras- MAPK and PI3K/Akt/ NF-κB cellular signal transduction pathways that lead to cancer development and progression. HER2 is, therefore, presumed as one of the key targets for the development of tumor-specific therapies. Several preclinical have been developed that function by inhibiting the HER2 tyrosine kinase activity through the prevention of the dimerization process. Most HER2 inhibitors act as ATP competitors and prevent the process of phosphorylation, and abort the cell cycle progression and proliferation. In this review, the clinical drug candidates and potent pre-clinical newly developed molecules are described, and the core chemical scaffolds typically responsible for anti-HER2 activity are deciphered. In addition, the monoclonal antibodies that are either used in monotherapy or in combination therapy against HER2-positive cancer are briefly described. The identified key moieties in this study could result in the discovery of more effective HER2-targeted anticancer drug molecules and circumvent the development of resistance by HER2-specific chemotherapeutics in the future.
HER2 是一种膜受体酪氨酸激酶，在多种人类恶性肿瘤中过度表达，特别是乳腺癌。HER2 过度表达导致 Ras-MAPK 和 PI3K/Akt/NF-κB 细胞信号转导通路的激活，从而导致癌症的发生和发展。因此，HER2 被认为是肿瘤特异性治疗开发的关键靶点之一。已经开发了几种通过抑制 HER2 酪氨酸激酶活性来发挥作用的临床前药物，通过阻止二聚化过程来实现。大多数 HER2 抑制剂作为 ATP 竞争物，防止磷酸化过程，并阻止细胞周期的进展和增殖。在这篇综述中，描述了临床候选药物和新开发的有潜力的临床前分子，揭示了通常负责抗 HER2 活性的核心化学支架。此外，还简要描述了单药或联合治疗 HER2 阳性癌症的单克隆抗体。在这项研究中确定的关键部分可能会导致发现更有效的针对 HER2 的抗癌药物分子，并在未来规避 HER2 特异性化疗药物耐药性的发展。
