Journal Article

Targeting cancer glutamine dependency with a first-in-class inhibitor of the mitochondrial glutamine transporter SLC1A5_var

Lim, Seonghun, Han, Jung Min, Lee, Mirim, Parajulee, Apeksha, Yoo, Hee Chan, Min, Do Sik, Lee, Yechan, Yu, Ya Chun, Kang, Mincheol, Kim, Kuglae, Namkung, Wan, Choi, Junjeong, Woo, Sang Myung, Kwon, Doru, Kim, Yun-Hee, Kim, Nam Doo, Sung, Yulseung

2025

Overview

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. Glutamine addiction is a hallmark of many cancers. iMQT_020, a first-in-class allosteric inhibitor of the mitochondrial glutamine transporter SLC1A5_var, disrupts glutamine-dependent mitochondrial metabolism, selectively killing cancer cells and enhancing immune checkpoint inhibitor efficacy.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13 / 13/31 / 14 / 14/33 / 38 / 49 / 64 / 692/4017 / 692/4028/67/2327 / 96 / 96/31 / Addictions / Allosteric properties / Allosteric Regulation - drug effects / Amino Acid Transport System ASC - antagonists & inhibitors / Amino Acid Transport System ASC - chemistry / Amino Acid Transport System ASC - genetics / Amino Acid Transport System ASC - metabolism / Amino acids / Animals / Antineoplastic Agents - pharmacology / B7-H1 Antigen - genetics / B7-H1 Antigen - metabolism / Cancer / Cancer therapies / Cell Line, Tumor / Cell Proliferation - drug effects / Effectiveness / Glutamine / Glutamine - metabolism / Homeostasis / Humanities and Social Sciences / Humans / Immune checkpoint inhibitors / Metabolism / Metabolites / Mice / Minor Histocompatibility Antigens - chemistry / Minor Histocompatibility Antigens - genetics / Minor Histocompatibility Antigens - metabolism / Mitochondria / Mitochondria - drug effects / Mitochondria - metabolism / multidisciplinary / Neoplasms - drug therapy / Neoplasms - metabolism / Neoplasms - pathology / Oxidative phosphorylation / Oxidative Phosphorylation - drug effects / PD-L1 protein / Phosphorylation / Proteins / Science / Science (multidisciplinary)