Liolios Christos, Laros George, Georgiou Kyriakos, Kolokouris Antonios
Laboratory of Medicinal Chemistry, Section of Pharmaceutical Chemistry, Department of Pharmacy, National and Kapodistrian University of Athens (NKUA), Panepistimiopolis-Zografou, 15771 Athens, Greece.
J Med Chem. 2025 Jun 26;68(12):12296-12330. doi: 10.1021/acs.jmedchem.4c02626. Epub 2025 Jun 12.
Prostate-specific membrane antigen (PSMA) or glutamate carboxypeptidase II (GCPII) is a promising target for metastatic castration-resistant prostate cancer (mCRPC) due to its high expression in prostate cancer cell membranes and low expression in normal tissues. Ligand-targeted drugs (LTDs) targeting PSMA are gaining popularity for their high affinity, specificity, and ease of synthesis. LTDs consist of a small molecule targeting PSMA and carrying the cytotoxic agent to the cancer cells, which is then released through a cleavable linker (enzymatically or chemically cleaved) into the tumor tissue. Several PSMA-targeting LTDs have demonstrated promising results in both and studies, and a few are in clinical trials, showing potential to outperform the unmodified cytotoxic drugs. This article focuses on their structures and preclinical studies while discussing clinical data for a few very promising PSMA-targeting LTDs in detail.
前列腺特异性膜抗原（PSMA）或谷氨酸羧肽酶II（GCPII）是转移性去势抵抗性前列腺癌（mCRPC）的一个有前景的靶点，因为它在前列腺癌细胞膜中高表达，而在正常组织中低表达。靶向PSMA的配体靶向药物（LTDs）因其高亲和力、特异性和易于合成而越来越受欢迎。LTDs由一个靶向PSMA的小分子组成，该小分子将细胞毒性剂携带到癌细胞，然后通过可裂解的连接子（酶促或化学裂解）释放到肿瘤组织中。几种靶向PSMA的LTDs在体外和体内研究中都显示出了有前景的结果，并且有一些正在进行临床试验，显示出优于未修饰的细胞毒性药物的潜力。本文重点介绍它们的结构和临床前研究，同时详细讨论几种非常有前景的靶向PSMA的LTDs的临床数据。
