State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan, 610041, People's Republic of China.
Department of Respiratory and Critical Care Medicine, West China Hospital of Sichuan University, Chengdu, Sichuan, 610041, People's Republic of China.
Biochem Biophys Res Commun. 2019 Apr 2;511(2):381-386. doi: 10.1016/j.bbrc.2019.02.064. Epub 2019 Feb 22.
Microtubules (MTs) is one of the most important proteins in eukaryotic cells and plays a key role in the maintenance of cell morphology and cell division. The discovery and development of small molecule drugs targeting MTs has always been an important direction of anti-cancer research. Nowadays 4-Aryl-4H-chromenes have emerged as potent microtubule-targeting agents (MTAs) for various cancers. Crolibulin, a derivative of 4-Aryl-4H-chromenes, which has been progressed to Phase I/II clinical testing's for anaplastic thyroid cancer with the National Cancer Institute. However, the design and development of 4-Aryl-4H-chromenes family drugs have been hindered for a long time by the lack of structural information of the tubulin-agent complex. Here we report a 2.5 Å crystal structure of tubulin complexed with crolibulin. This complex structure reveals the interactions between crolibulin and tubulin, helps explain the results of the structure-activity-relationship (SAR) studies and provides a solid structural basis for the design and development of new 4-Aryl-4H-chromenes derivatives as MTAs.
微管（MTs）是真核细胞中最重要的蛋白质之一，在维持细胞形态和细胞分裂方面起着关键作用。靶向 MTs 的小分子药物的发现和开发一直是抗癌研究的重要方向。如今，4-芳基-4H-色烯已成为各种癌症的有效微管靶向剂（MTAs）。Crolibulin 是 4-芳基-4H-色烯的衍生物，已被美国国立癌症研究所推进到用于间变性甲状腺癌的 I/II 期临床试验。然而，4-芳基-4H-色烯类药物的设计和开发长期以来一直受到缺乏微管蛋白-药物复合物结构信息的阻碍。在这里，我们报告了与 crolibulin 结合的微管蛋白的 2.5 Å 晶体结构。该复合物结构揭示了 crolibulin 与微管蛋白之间的相互作用，有助于解释结构-活性关系（SAR）研究的结果，并为设计和开发新的 4-芳基-4H-色烯衍生物作为 MTAs 提供了坚实的结构基础。
