ABSTRACT Cancer patients are highly susceptible to fungal infections due to their compromised health status and immunosuppression. To identify novel antifungal agents, we conducted a cell‐based phenotypic screening against an in‐house chemical library comprising hundreds of kinase inhibitors. Through this screening, G‐749—a clinically active FLT3 inhibitor currently in Phase I trial for leukemia treatment—was identified to exhibit moderate and broad‐spectrum antifungal activity. G‐749 demonstrated minimum inhibitory concentrations (MICs) ranging from 4 to 16 µg/mL against seven tested fungal strains. Notably, G‐749 exhibited potent antifungal activity against Candida tropicalis with MIC values of 4 µg/mL. Moreover, G‐749 demonstrated fungicidal effects at 32 µg/mL and a synergistic inhibitory effect when combined with amphotericin B. In addition, it inhibited Candida albicans ( C. albicans ) biofilm formation and damaged the mature biofilms in a concentration‐dependent manner. Mechanism studies indicated that the antifungal activity of G‐749 was associated with increased intracellular reactive oxygen species accumulation, ultrastructural damage to intracellular organelles and cytoplasmic integrity, and induction of apoptosis. Taken together, G‐749 was identified as a promising lead structure for discovery of novel antifungal agents.
Liu et al. (Sun,) studied this question.