Authors
Yigui Li, Rui Xu, Xinhua Xie, Wanzhu Zhao, Linchong He, Tao Zheng, Wuyi Zhang, Pinghua Sun, Jun Xu, Xin Chen
Published in
Bioorganic & medicinal chemistry letters. Pages 130777. Sep 10, 2026. Epub Sep 10, 2026.
Abstract
Constitutive activation of STAT3 and dysregulation of the thioredoxin reductase 1 (TrxR1) system are deeply implicated in the pathogenesis, progression, and drug resistance of colorectal cancer (CRC). Herein, guided by a pharmacophore fusion strategy, we rationally designed and synthesized a novel series of STAT3/TrxR1 dual inhibitors by integrating the naphthoquinone core of Napabucasin with the bioactive scaffold of curcumin. Systematic structure-activity relationship (SAR) investigations identified the cinnamoyl-type derivative LF39 as the optimal lead compound. LF39 exhibited potent antiproliferative activity against HCT116 cells with an IC50 value of 0.48 ± 0.05 μM and significantly abrogated clonogenic survival in a dose-dependent manner. Mechanistic studies elucidated that LF39 effectively induced programmed cell death via apoptosis. Crucially, LF39 exhibited direct TrxR1 enzymatic inhibition (IC50 = 0.515 μM) and effectively abrogated intracellular p-STAT3 signaling. Furthermore, molecular docking combined with 100 ns molecular dynamics simulations validated the highly stable dual-binding networks of LF39 within both the STAT3 SH2 domain and the TrxR1 active site. Preliminary biosafety evaluations demonstrated that LF39 possesses excellent hemocompatibility with negligible hemolytic toxicity at concentrations up to 100 μM. Taken together, these findings structurally support the STAT3/TrxR1 polypharmacology strategy and present LF39 as a highly promising, rationally designed lead compound for CRC intervention.
PMID:
42722114
Bibliographic data and abstract were imported from PubMed on 11 Sep 2026.
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