REarranged during Transfection(RET)基因是一个编码转膜受体酪氨酸激酶的已确定的致癌基因，与多种癌症的发病和进展相关。在许多成人癌症中已经鉴定出致癌性的RET突变和基因融合，包括髓质和乳头状甲状腺癌、肺腺癌、结肠癌和乳腺癌等。虽然在儿科实体肿瘤中基因突变的RET异常发生较少，但已经发现RET表达增加与儿童实体肿瘤（如神经母细胞瘤）患者的不良预后有关，因此引起了在这些儿童中采用RET抑制作为治疗方式的兴趣。目前有一些正在用于癌症患者的激酶抑制剂具有RET抑制活性，但这些抑制剂也显示出对其他激酶的活性，导致不良副作用，并限制了其安全性和疗效。近年来的研究工作集中在开发更具特异性的RET抑制剂，但由于激酶结合口袋之间的高度保守性，特异性仍然是一项药物设计的挑战。在本文中，我们回顾了RET作为神经母细胞瘤潜在治疗靶点的背景，并介绍了近期对成人和儿童进行RET抑制剂安全性和疗效评估的临床试验和临床前研究的结果。我们还提出一种利用药物设计中的化学现象旋异构体来开发特异性的RET抑制剂的新方法，并提供了对神经母细胞瘤肿瘤细胞的一种新RET抑制剂的疗效初步数据。版权所有©2023 Elsevier Inc.

The RET (REarranged during Transfection) gene, which encodes for a transmembrane receptor tyrosine kinase, is an established oncogene associated with the etiology and progression of multiple types of cancer. Oncogenic RET mutations and rearrangements resulting in gene fusions have been identified in many adult cancers, including medullary and papillary thyroid cancers, lung adenocarcinomas, colon and breast cancers, and many others. While genetic RET aberrations are much less common in pediatric solid tumors, increased RET expression has been shown to be associated with poor prognosis in children with solid tumors such as neuroblastoma, prompting an interest in RET inhibition as a form of therapy for these children. A number of kinase inhibitors currently in use for patients with cancer have RET inhibitory activity, but these inhibitors also display activity against other kinases, resulting in unwanted side effects and limiting their safety and efficacy. Recent efforts have been focused on developing more specific RET inhibitors, but due to high levels of conservation between kinase binding pockets, specificity remains a drug design challenge. Here, we review the background of RET as a potential therapeutic target in neuroblastoma tumors and the results of recent preclinical studies and clinical trials evaluating the safety and efficacy of RET inhibition in adults and children. We also present a novel approach to drug discovery leveraging the chemical phenomenon of atropisomerism to develop specific RET inhibitors and present preliminary data demonstrating the efficacy of a novel RET inhibitor against neuroblastoma tumor cells.Copyright © 2023. Published by Elsevier Inc.