1.Preclinical Pharmacological and Toxicological Evaluation of SB5794, a Novel Aryl Hydrocarbon Receptor Modulator on the Kynurenine–AhR Axis
Daewon CHA ; Soo-Jung CHOI ; Hyunwoo PARK ; Dae Young LEE ; Min Sung JOO ; Wonhyung LEE ; Jungsang PARK ; Eunhye LEE ; Hakwon KIM
Biomolecules & Therapeutics 2026;34(1):146-153
Conventional aryl hydrocarbon receptor (AhR) antagonists, which play a critical role in modulating tumor immune evasion, have shown limited clinical translation due to poor solubility, restricted systemic exposure, and dose-limiting toxicities. To overcome these limitations, we developed SB5794, a phosphate prodrug of the potent AhR antagonist SB2617, designed to improve aqueous solubility and pharmacokinetic properties. SB5794 exhibited markedly enhanced solubility and achieved more than six-fold higher systemic exposure in mice compared with SB2617, while fully retaining its in vitro AhR antagonistic activity. In syngeneic tumor models, SB5794 significantly inhibited tumor growth, and its combination with anti–PD-1 therapy further enhanced antitumor efficacy. However, repeated-dose studies revealed dose-dependent histopathological changes in the gastrointestinal tract, liver, and immune organs. Collectively, these findings demonstrate that SB5794 possesses improved drug-like properties and strong immunomodulatory activity, supporting its potential as a next-generation AhR-targeted immunotherapeutic candidate.
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