Structural Optimization Strategy for α,β-Unsaturated Ketone TrxR Inhibitors: From Enhanced Pharmacokinetics to...

Thioredoxin reductase (TrxR), a master regulator of intracellular redox homeostasis, is a validated antitumor target. α,β-Unsaturated ketones are potent irreversible TrxR inhibitors with robust in vitro anticancer activity, yet their clinical translation is hindered by critical druggability deficits: poor pharmacokinetics (low solubility, metabolic instability, and low bioavailability) and insufficient tumor selectivity (off-target toxicity and weak tumor tropism). This review systematically summarizes structural optimization strategies to address these limitations. To improve pharmacokinetics, core tactics include introducing polar heterocycles/hydrophilic groups, modifying skeletons, replacing labile moieties, and hybridizing pharmacophores with subcellular targeting motifs. To enhance tumor selectivity, electronic effect modulation, lipophilicity tuning, scaffold rigidification, tumor-targeting moiety conjugation, and electrophilic center regulation reduce off-target effects. Additionally, tumor-specific redox properties are harnessed to boost intratumoral enrichment. The review further highlights current limitations (e.g., overreliance on natural product modifications, lack of universal SAR frameworks, and inadequate ADME regulation) and prospects future directions: structure-based rational design, tumor microenvironment-responsive prodrugs, multi-target synergism, reversible-irreversible switchable inhibitors, and nanodelivery integration. Collectively, these optimizations lay a theoretical foundation for developing safe, effective TrxR inhibitors to advance precision cancer therapy.