Department of Pharmacy, Yantai University Hospital, Yantai, 264003, China.
School of Pharmacy, Yantai University, Yantai, 264005, China.
Mini Rev Med Chem. 2023;23(18):1797-1805. doi: 10.2174/1389557523666230220121648.
As a novel bio-targeting antitumor agent, an antibody-drug conjugate (ADC) combines the high selectivity of monoclonal antibody and potent cytotoxicity of drug or payload. It can expand the scope of clinical application of small molecule drugs. Tubulysin and its bio-precursor pretubulysin (PT) are potent tubulin-binding antitumor drugs. Due to the excellent antitumoral, antimetastatic, antiangiogenic, and anti-multidrug resistance properties, Tubulysins or PT is believed to be a promising cancer therapeutic approach. Currently, the modifications of tubulysin are centering on the C-11 acetoxyl and N,O-acetal groups, and numerous promising payloads are identified. There are at least 5 sites to introduce appropriate drug linkers in tubulysin and PT for connecting the antibodies. The possible sites of attachment are located in Mep, Tuv, or Tup parts. Cleavage and non-cleavage linkers are used in these ADCs. The chemical reactions involved in the final conjugation of antibody and linkerpayload (LP) are cysteine, lysine, site-specific, and click chemistry reactions. In this article, the recent development of ADCs with tubulysins as the payloads is reviewed, with the hope of providing a reference and future strategies for developing new ADSs.
作为一种新型的生物靶向抗肿瘤药物，抗体药物偶联物（ADC）结合了单克隆抗体的高选择性和药物或有效载荷的强大细胞毒性。它可以扩大小分子药物的临床应用范围。微管蛋白结合抗肿瘤药物tubulysin 和其生物前体 pretubulysin（PT）具有很强的抗肿瘤、抗转移、抗血管生成和抗多药耐药性的特性，因此被认为是一种很有前途的癌症治疗方法。目前，tubulysin 的修饰主要集中在 C-11 乙酰氧基和 N,O-缩醛基团上，并确定了许多有前途的有效载荷。在 tubulysin 和 PT 中至少有 5 个部位可以引入合适的药物连接子来连接抗体。可能的附着部位位于 Mep、Tuv 或 Tup 部分。这些 ADC 中使用了可裂解和不可裂解的连接子。在抗体和连接子有效载荷（LP）的最终缀合过程中涉及的化学反应有半胱氨酸、赖氨酸、特异性和点击化学反应。本文综述了以 tubulysin 为有效载荷的 ADC 的最新研究进展，希望为开发新型 ADC 提供参考和未来策略。
