Design, synthesis, and evaluation of anti-solid-tumor activity of niclosamide-based STAT3/HDAC dual-target inhibitors

  • Bioorg Chem. 2026 Jul 25:181:110272. doi: 10.1016/j.bioorg.2026.110272.
Yuchen Shi  1 ,  Qihao Zhang  2 ,  Chenxi Wang  1 ,  Zipeng Lu  3 ,  Fangfang Chen  3 ,  Liu Han  3 ,  Zhouyang Xu  1 ,  Yuan Zhang  1 ,  Shumei Ma  4 ,  Faqing Ye  5 ,  Xuebao Wang  6
Affiliations
  • 1. School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
  • 2. Department of Pharmaceutical Engineering, College of Biomedical Science, Daegu Catholic University, Gyeongsan 38430, Republic of Korea.
  • 3. School of Public Health, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
  • 4. School of Public Health, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China. Electronic address: [email protected].
  • 5. School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China. Electronic address: [email protected].
  • 6. School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China. Electronic address: [email protected].
PMID: 42526131 DOI: 10.1016/j.bioorg.2026.110272
Abstract

Inspired by reports that HDAC blockade can trigger compensatory activation of the LIFR-JAK1-STAT3 axis in solid tumors, we designed and synthesized a series of niclosamide-based STAT3/HDAC dual-target inhibitor candidates by incorporating a SAHA-derived hydroxamate zinc-binding group into the pleiotropic, STAT3-modulating niclosamide scaffold. Biological evaluation identified NS06 as the best-balanced analogue, with IC50 values of 1.49 and 1.41 μM against MDA-MB-231 and HCT116 cells, respectively. Mechanistic studies showed that NS06 bound STAT3 in vitro (SPR, KD = 5.82 μM), suppressed STAT3 phosphorylation, and inhibited HDAC1, HDAC3, and HDAC6 with IC50 values of 129.1, 451.2, and 230.4 nM, respectively, while showing limited inhibition of HDAC4 and HDAC11 in the primary screen. NS06 also increased histone H3 acetylation, induced Apoptosis, and inhibited migration and colony formation. In addition, NS06 retained antiproliferative activity in a 3D tumor spheroid model and showed improved Caco-2 permeability together with moderate liver microsomal stability (t1/2 ≈ 48.6 min in rat liver microsomes). Docking and 100-ns molecular dynamics simulations further supported chemically plausible binding modes in the HDAC1 catalytic pocket and the STAT3 SH2 domain. Overall, these findings support niclosamide as a tractable scaffold for mechanism-driven STAT3/HDAC dual-target inhibitor design and identify NS06 as a promising lead for further optimization against solid tumors.

Keywords
Anticancer agent; Niclosamide; STAT3/HDAC dual-target inhibitor; Solid tumors.
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