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<p>The therapeutic target tubulin, which is of great clinical significance, was previously believed to be an undegradable protein by PROTAC technology. Based on the fact that tubulin-targeting agents have been successfully developed as chemotherapeutic drugs in cancer treatment for decades, it is anticipated that research on tubulin PROTACs will address the limitations of tubulin inhibitor, including resistance and toxicity, as well as revitalize this “old” target. Herein, a series of novel tubulin degraders were designed and synthesized by connecting CA-4 with CRBN ligands through linkers of varied lengths and compositions. One active degrader <b>C02</b> was identified, which achieved a DC<sub>50</sub> value of 1.73 μM and 1.38 μM for α- and β-tubulin respectively in A549 cells. Further biological evaluation has shown that <b>C02</b> could trigger the degradation of the αβ-tubulin in a ubiquitin-proteasome dependent manner. In addition, <b>C02</b> was discovered to arrest cell cycle at G2/M phase, induced ROS accumulation, inhibited migration and eventually apoptosis of cancer cells.</p><p></p>

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Design and synthesis of Cereblon-based PROTAC as novel potent degraders of α/β-tubulin

  • 期刊论文

  • 发表日期：

    2025年12月27日

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  • Yinuo Wang,
  • Liping Chen,
  • Ruili Ma,
  • Mei Zhao,
  • Mingmei Guo,
  • Xiaoya Wu,
  • Hua Yang,
  • Ling Zhu,
  • Moran Sun

摘要

The therapeutic target tubulin, which is of great clinical significance, was previously believed to be an undegradable protein by PROTAC technology. Based on the fact that tubulin-targeting agents have been successfully developed as chemotherapeutic drugs in cancer treatment for decades, it is anticipated that research on tubulin PROTACs will address the limitations of tubulin inhibitor, including resistance and toxicity, as well as revitalize this “old” target. Herein, a series of novel tubulin degraders were designed and synthesized by connecting CA-4 with CRBN ligands through linkers of varied lengths and compositions. One active degrader C02 was identified, which achieved a DC50 value of 1.73 μM and 1.38 μM for α- and β-tubulin respectively in A549 cells. Further biological evaluation has shown that C02 could trigger the degradation of the αβ-tubulin in a ubiquitin-proteasome dependent manner. In addition, C02 was discovered to arrest cell cycle at G2/M phase, induced ROS accumulation, inhibited migration and eventually apoptosis of cancer cells.