Maderna Andreas, Leverett Carolyn A
Pfizer Worldwide Research and Development, Worldwide Medicinal Chemistry, Oncology, Eastern Point Road, Groton, Connecticut 06340, United States.
Mol Pharm. 2015 Jun 1;12(6):1798-812. doi: 10.1021/mp500762u. Epub 2015 Mar 5.
Dolastatin 10 is a powerful antineoplastic agent and microtubule inhibitor that was discovered by Pettit et al. and published in 1987. Since then, many research groups have engaged in SAR studies of synthetic analogues, termed "auristatins". It was eventually discovered that auristatins are of great value as payloads in antibody drug conjugates (ADCs), which led to the FDA-approved ADC brentuximab vedotin (Seattle Genetics). Currently, over 30 ADCs in clinical trials employ auristatins as payloads, and there is a great interest in the research community, both on academic and industrial sides, to further study these analogues. This review will provide an overview of the recent advancements in auristatin development spanning a time frame of about the past ten years. The main focus will be to describe structural changes made to the auristatin peptide and their resulting biological activities in tumor cell proliferation assays. Selected ADC examples will also be described.
多拉司他汀10是一种强效抗肿瘤药物和微管抑制剂，由佩蒂特等人发现并于1987年发表。从那时起，许多研究小组都参与了对合成类似物“奥瑞他汀”的构效关系研究。最终发现，奥瑞他汀作为抗体药物偶联物（ADC）的有效载荷具有很大价值，这促成了美国食品药品监督管理局（FDA）批准的ADC药物本妥昔单抗（西雅图遗传学公司生产）。目前，超过30种处于临床试验阶段的ADC药物使用奥瑞他汀作为有效载荷，学术界和工业界的研究团体都对进一步研究这些类似物有着浓厚兴趣。本综述将概述奥瑞他汀在过去大约十年时间里的最新研发进展。主要重点将是描述对奥瑞他汀肽所做的结构改变及其在肿瘤细胞增殖试验中产生的生物学活性。还将介绍一些选定的ADC实例。
