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

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Abstract
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.
Funding Information
  • National Natural Science Foundation of China (82073318, 81703553, 81803755)
  • Sichuan Science and Technology Program (2019YFS0003)
  • China Postdoctoral Science Foundation (2018T110984, 2017M610607)
  • National Major Scientific and Technological Special Project for ‘Significant New Drugs Development’ (2018ZX09201018-021)
  • Post-Doctor Research Project, West China Hospital, Sichuan University (2018HXBH057, 2018HXBH011)

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