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

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. [Display omitted] • A series of CRBN-based PROTACs have been firstly synthesized as tubulin degrader. • W13 induces α/β/β3-tubulin in A549S and A549T cells via UPS-dependent manners. • The RI values of W13 on drug-resistant cancer cells was superior to that of Taxol. • The tumor growth inhibition values of W13 were 65.8% on A549T xenograft tumor model. [ABSTRACT FROM AUTHOR]