A Rationale for Drug Design Provided by Co-Crystal Structure of IC261 in Complex with Tubulin.


Xian J(1), Bu F(1)(2), Wang Y(2), Long F(3), Zhang Z(2), Wu C(1)(2), Tao Y(2), Wang T(3), Wang G(1)(2).
Author information:
(1)Department of Clinical Research Management, Innovation Center of Nursing Research, Nursing Key Laboratory of Sichuan Province, West China Hospital, Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu 610041, China.
(2)Precision Medicine Research Center, Department of Respiratory and Critical Care Medicine, West China Hospital, Sichuan University, Chengdu 610041, China.
(3)Department of Pharmacy, Sichuan Cancer Hospital & Institution, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610041, China.


Microtubules composed of α/β tubulin heterodimers are an essential part of the cytoskeleton of eukaryotic cells and are widely regarded as targets for cancer chemotherapy. IC261, which is discovered as an ATP-competitive inhibitor of serine/threonine-specific casein kinase 1 (CK1), has shown its inhibitory activity on microtubule polymerization in recent studies. However, the structural information of the interaction between tubulin and IC261 is still unclear. Here, we provided a high-resolution (2.85 Å) crystal structure of tubulin and IC261 complex, revealed the intermolecular interaction between tubulin and IC261, and analyzed the structure-activity relationship (SAR). Subsequently, the structure of tubulin-IC261 complex was compared with tubulin-colchicine complex to further elucidate the novelty of IC261. Furthermore, eight optimal candidate compounds of new IC261-based microtubule inhibitors were obtained through molecular docking studies. In conclusion, the co-crystal structure of tubulin-IC261 complex paves a way for the design and development of microtubule inhibitor drugs.