State Key Laboratory of Biotherapy and Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, People's Republic of China.
School of Physical Science and Technology, Electron Microscopy Center of Lanzhou University, Lanzhou University, Lanzhou, 730000, People's Republic of China.
Biochem Biophys Res Commun. 2021 Aug 6;565:29-35. doi: 10.1016/j.bbrc.2021.05.086. Epub 2021 Jun 2.
Microtubule-targeting agents (MTAs) are the most commonly used anti-cancer drugs. At least fourteen microtubule inhibitors and ten antibody drug conjugates (ADCs) linking MTAs are approved by FDA for clinical use in cancer therapy. In current research, we determined the crystal structure of tubulysin analogue TGL in complex with tubulin at a high resolution (2.65 Å). In addition, we summarized all of the previously published high-resolution crystal structures of ligands in the vinca site to provide structural insights for the rational design of the new vinca-site ligands. Moreover, based on the aligned results of the vinca site ligands, we provided three possible routes for designing new tubulysin analogues, namely macrocyclization between the N-14 side chain and the N-9 side chain, the hybird of tubulysin M and phomopsin A, and growing new aryl group at C-21. These designed structures will inspire the development of new MTAs or payloads in cancer therapy.
微管靶向剂（MTAs）是最常用的抗癌药物。至少有 14 种微管抑制剂和 10 种连接 MTAs 的抗体药物偶联物（ADC）已被 FDA 批准用于癌症治疗的临床应用。在当前的研究中，我们确定了微管蛋白类似物 TGL 与微管蛋白复合物的晶体结构，分辨率高达 2.65 Å。此外，我们总结了所有以前发表的长春碱结合部位配体的高分辨率晶体结构，为合理设计新的长春碱结合部位配体提供了结构见解。此外，基于长春碱结合部位配体的对齐结果，我们提供了设计新的微管蛋白类似物的三种可能途径，即 N-14 侧链和 N-9 侧链之间的大环化、微管蛋白 M 和 phomopsin A 的杂交，以及在 C-21 上生长新的芳基基团。这些设计的结构将激发新的 MTAs 或癌症治疗中有效载荷的开发。
