Discovery of Selective Inhibitors for β-Actin Polymerization as Potential Anticancer Agents In Vitro and In Vivo

  • J Med Chem. 2026 Jun 11;69(11):13345-13366. doi: 10.1021/acs.jmedchem.6c00299.
Weixiong Chen  1 ,  Shilong Hao  1 ,  Donghui Sun  1 ,  Jiarui Chang  2 ,  Meng Li  1 ,  Zongjing Hu  1 ,  Jinhua Liu  1 ,  Yikai Xu  1 ,  Ya Gao  2 ,  Tong Zhu  1 ,  Shunying Liu  1  3
Affiliations
  • 1. Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, China.
  • 2. School of Mathematics, Physics and Statistics, Shanghai University of Engineering Science, Shanghai 201620, China.
  • 3. Chongqing Institute of East China Normal University, Chongqing 401120, China.
PMID: 42212343 DOI: 10.1021/acs.jmedchem.6c00299
Abstract

No selective actin inhibitor has been developed due to the high homology of actin isoforms. Given the distributions of cysteine residues among actin isoforms, we propose the covalent small-molecule targeting approach offers a distinct path to achieve isoform selectivity. Combining phenotypic screening of our in-house covalent compound library and structural optimizations, we identified a novel and selective β-actin inhibitor C25. ABPP protein affinity enrichment and mechanistic investigations discovered C25 specifically targeted to β-actin but not α- or γ-actin and inhibited its polymerization to disrupt the actin Cytoskeleton and lead to cell death in143B cells. C25 exhibits potent Anticancer activity both in vitro (IC50 = 0.015 μM) and in vivo (TGI = 66%) and shows no obvious toxicity at the tested dosage. To our knowledge, C25 represents the first selective inhibitor of β-actin. This provides valuable insights and a foundation for subsequent research on the selectivity of actins and related drug discovery.

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