2. Academic Validation
  3. Discovery of the cereblon-recruiting tubulin PROTACs effective in overcoming Taxol resistance in vitro and in vivo

Discovery of the cereblon-recruiting tubulin PROTACs effective in overcoming Taxol resistance in vitro and in vivo

  • Eur J Med Chem. 2024 Feb 5:265:116067. doi: 10.1016/j.ejmech.2023.116067.
Hua Yang 1,  Jinling Qin 1,  Yuanyuan Pei 1,  Sumeng Guan 1,  Mei Zhao 1,  Yingge Wang 1,  Yongfang Yao 1,  Yongtao Duan 2,  Moran Sun 3
Affiliations

Affiliations

  • 1 School of Pharmaceutical Sciences, and Institute of Drug Discovery & Development, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan, 450001, China.
  • 2 Henan Provincial Key Laboratory of Children's Genetics and Metabolic Diseases, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou University, Zhengzhou, 450018, China. Electronic address: duanyongtao860409@163.com.
  • 3 School of Pharmaceutical Sciences, and Institute of Drug Discovery & Development, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan, 450001, China. Electronic address: sunmr@zzu.edu.cn.
PMID: 38171146 DOI: 10.1016/j.ejmech.2023.116067
Abstract

Overexpression of β3-tubulin is a common occurrence in human tumors and is associated with resistance to microtubule-targeting agents. PROTAC strategy has demonstrated significant potential in overcoming drug resistance. Herein, we report the discovery of W13 as the first PROTAC against tubulin, which was created by connecting a CRBN ligand to the widely recognized microtubule-destabilizing agent CA-4. Notably, it retains the inhibitory activity of the parental CA-4 and further exhibits substantial degradation of α/β/β3-tubulin in both A549 and A549/Taxol cell lines. The degradation of tubulin was subsequently verified to be mediated by the ubiquitin-proteasome system. Importantly, tumor xenograft research clearly showed W13's promising antitumor activity against human lung Cancer. Taken together, the discovery of W13 demonstrated the practicality and feasibility of PROTAC targeting tubulin, hence establishing a potential therapeutic approach for treating NSCLC caused by the overexpression of β3-tubulin.

Keywords

CA-4; Cereblon; PROTACs; Taxol resistance; Tubulin.

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