Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan 528400, China.
Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
J Med Chem. 2024 Sep 26;67(18):16018-16034. doi: 10.1021/acs.jmedchem.4c01525. Epub 2024 Sep 13.
TSHR is a member of the glycoprotein hormone receptors, a subfamily of class A G-protein-coupled receptors and plays pivotal roles in various physiological and pathological processes, particularly in thyroid growth and hormone production. The aberrant TSHR function has been implicated in several human diseases including Graves' disease and orbitopathy, nonautoimmune hyperthyroidism, hypothyroidism, cancer, neurological disorders, and osteoporosis. Consequently, TSHR is recognized as an attractive therapeutic target, and targeting TSHR with small-molecule modulators including agonists, antagonists, and inverse agonists offers great potential for drug discovery. In this perspective, we summarize the structures and biological functions of TSHR as well as the recent advances in the development of small-molecule TSHR modulators, highlighting their chemotypes, mode of actions, structure-activity relationships, characterizations, in vitro/in vivo activities, and therapeutic potential. The challenges, new opportunities, and future directions in this area are also discussed.
促甲状腺激素受体（TSHR）是糖蛋白激素受体家族的一员，属于 A 类 G 蛋白偶联受体亚家族，在多种生理和病理过程中发挥关键作用，特别是在甲状腺生长和激素产生中。异常的 TSHR 功能与多种人类疾病有关，包括格雷夫斯病和眼病、非自身免疫性甲状腺功能亢进症、甲状腺功能减退症、癌症、神经紊乱和骨质疏松症。因此，TSHR 被认为是一个有吸引力的治疗靶点，用小分子调节剂（包括激动剂、拮抗剂和反向激动剂）靶向 TSHR 为药物发现提供了巨大的潜力。在这篇观点文章中，我们总结了 TSHR 的结构和生物学功能，以及小分子 TSHR 调节剂开发的最新进展，重点介绍了它们的化学型、作用模式、结构-活性关系、特性、体外/体内活性和治疗潜力。还讨论了该领域的挑战、新机遇和未来方向。
