Wogonin-derived chemotype enables discovery of novel GLS1 inhibitors with potent antitumor activity.

AIMS: This study evaluates LX-191, a wogonin-derived glutaminase-1 (GLS1) inhibitor featuring a non-BPTES chemotype, designed to overcome the limitations of existing GLS1-targeted therapies.

MATERIALS AND

METHODS

Following targeted screening to identify the flavone-based inhibitor LX-191, we assessed its GLS1 inhibitory potency and antiproliferative effects in A549 and HCT116 cells. In vivo therapeutic efficacy was evaluated using an A549 xenograft model, alongside mechanistic studies to determine its impact on oncogenic signaling.

RESULTS

LX-191 effectively inhibited GLS1 (IC50 = 15.17 μM) and demonstrated potent antiproliferative activity in A549 and HCT116 cells. In A549 xenografts, LX-191 achieved 50.3% tumor growth inhibition at 10 mg/kg, outperforming CB-839 (21.6%) under identical conditions. Mechanistically, LX-191 attenuated glutamine metabolism while concurrently suppressing signal transducer and activator of transcription 3 (STAT3) and mammalian target of rapamycin (mTOR) signaling, leading to G1 phase cell cycle arrest and induction of autophagy.

CONCLUSIONS

The findings establish LX-191 as a promising flavone-based, non-BPTES lead for GLS1 inhibition, exhibiting multi-pathway antitumor activity both in vitro and in vivo. This work provides a tractable lead compound for the development of next-generation GLS1 therapeutics.