National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, Nanjing University of Chinese Medicine, 138 Xianlin Road, Nanjing, Jiangsu 210023, China.
School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, 138 Xianlin Road, Nanjing, Jiangsu 210023, China.
J Med Chem. 2024 Mar 28;67(6):4346-4375. doi: 10.1021/acs.jmedchem.3c02319. Epub 2024 Mar 14.
Over the past decades, the role of rearranged during transfection (RET) alterations in tumorigenesis has been firmly established. RET kinase inhibition is an essential therapeutic target in patients with RET-altered cancers. In clinical practice, initial efficacy can be achieved in patients through the utilization of multikinase inhibitors (MKIs) with RET inhibitory activity. However, the effectiveness of these MKIs is impeded by the adverse events associated with off-target effects. Recently, many RET-selective inhibitors, characterized by heightened specificity and potency, have been developed, representing a substantial breakthrough in the field of RET precision oncology. This Perspective focuses on the contemporary understanding of RET mutations, recent advancements in next-generation RET inhibitors, and the challenges associated with resistance to RET inhibitors. It provides valuable insights for the development of next-generation MKIs and selective RET inhibitors.
在过去的几十年中，重排过程中易位（RET）改变在肿瘤发生中的作用已得到充分确立。RET 激酶抑制是 RET 改变的癌症患者的重要治疗靶点。在临床实践中，通过使用具有 RET 抑制活性的多激酶抑制剂（MKIs），可以在患者中实现初始疗效。然而，这些 MKIs 的有效性受到与脱靶效应相关的不良反应的阻碍。最近，许多具有更高特异性和效力的 RET 选择性抑制剂已经开发出来，这是 RET 精准肿瘤学领域的重大突破。本观点重点介绍了对 RET 突变的当代理解、新一代 RET 抑制剂的最新进展以及对 RET 抑制剂耐药性的挑战。它为下一代 MKIs 和选择性 RET 抑制剂的开发提供了有价值的见解。
