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Development of a first-in-class inhibitor of the mitochondrial glutamine transporter SLC1A5_var to target glutamine dependency in cancer

ABSTRACT:

The mitochondrial glutamine transporter SLC1A5_var plays a central role in the metabolic reprogramming of cancer cells by facilitating glutamine import into mitochondria for energy production and redox homeostasis. Despite its critical function, the development of effective and selective inhibitors targeting SLC1A5_var has remained a significant challenge. Here, we introduce iMQT_020, a selective allosteric inhibitor identified through structure-based screening. iMQT_020 disrupts the trimeric assembly of SLC1A5_var, causing metabolic crisis in cancer cells and selectively suppressing their growth. Mechanistically, iMQT_020 reduces glutamine anaplerosis and oxidative phosphorylation, resulting in a broad disruption of cancer metabolism. Additionally, iMQT_020 treatment epigenetically upregulates PD-L1 expression, enhancing the efficacy of combination therapies with anti-PD-L1 immune checkpoint inhibitors. These findings highlight the therapeutic potential of targeting SLC1A5_var as a critical metabolic vulnerability in cancer and demonstrate that targeting allosteric interprotomer interactions is a novel and promising therapeutic strategy for cancer treatment.

INSTRUMENT(S): Liquid Chromatography MS - alternating - HILIC

PROVIDER: MTBLS12852 | MetaboLights | 2025-08-13

REPOSITORIES: MetaboLights

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			Action	DRS
	a_MTBLS12852_LC-MS_alternating_hilic_metabolite_profiling.txt	Txt
	i_Investigation.txt	Txt
	m_MTBLS12852_LC-MS_alternating_hilic_metabolite_profiling_v2_maf.tsv	Tabular
	s_MTBLS12852.txt	Txt

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Development of a first-in-class inhibitor of the mitochondrial glutamine transporter SLC1A5_var to target glutamine dependency in cancer

Project description:This study introduces iMQT_020, a first-in-class allosteric targeting of the mitochondrial glutamine transporter SLC1A5_var. By disrupting glutamine-dependent mitochondrial metabolism, iMQT_020 selectively induces cancer cell death and enhances the efficacy of immune checkpoint inhibitors. These findings highlight that SLC1A5_var is a critical metabolic vulnerability and a therapeutic target in glutamine-addicted cancers

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