2. Academic Validation
  3. Design, synthesis and biological evaluation of novel tubulin-targeting agents with a dual-mechanism for polymerization inhibition and protein degradation

Design, synthesis and biological evaluation of novel tubulin-targeting agents with a dual-mechanism for polymerization inhibition and protein degradation

  • Eur J Med Chem. 2024 Jun 5:272:116458. doi: 10.1016/j.ejmech.2024.116458.
Sibo Wang 1,  Jiahao Wang 1,  Xiankun Lu 2,  Meitong Liu 2,  Yue Liu 2,  Mi Li 2,  Xuejie Kong 3,  Lan Wu 4,  Qi Guan 5,  Weige Zhang 6
Affiliations

Affiliations

  • 1 Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang, 110016, China.
  • 2 School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang, 110016, China.
  • 3 Department of Geratology, The First Affiliated Hospital, Chinese Medical University, Shenyang, 110001, China.
  • 4 Department of Geratology, The First Affiliated Hospital, Chinese Medical University, Shenyang, 110001, China. Electronic address: wulan_2000@sina.com.
  • 5 School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang, 110016, China. Electronic address: guanqi@syphu.edu.cn.
  • 6 Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang, 110016, China. Electronic address: zhangweige2000@sina.com.
PMID: 38703557 DOI: 10.1016/j.ejmech.2024.116458
Abstract

Microtubules are recognized as one of the most vital and attractive targets in Anticancer therapy. The development of novel tubulin-targeting agents with a new action mechanism is imperative. Based on the hydrophobic tagging strategy, the molecular scaffold of tirbanibulin was selected as tubulin target-binding moiety, subsequent to which a series of target compounds were rationally designed by selecting various combinations of linkers and hydrophobic tags. A set of novel molecules were synthesized and most of them exhibited potent antiproliferative activity against tumor cells in vitro. The most active compound 14b inhibited polymerization of purified recombinant tubulin and induced degradation of α- and β-tubulin in MCF-7 cells. Notably, following treatment with compound 14b, an unexpected phenomenon of "microtubules fragmentation" was observed via immunofluorescence staining. Furthermore, compound 14b possessed antitumor activity in the 4T1 allograft models with TGI of 74.27 % without significant toxicity. In this work, we report the discovery of novel dual-mechanism tubulin-targeting agents.

Keywords

Dual-mechanism tubulin-targeting agents; Hydrophobic tagging; Protein degradation; Tubulin polymerization inhibition.

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