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

Yulseung Sung, Ya Chun Yu, Mirim Lee, Seonghun Lim, Yechan Lee, Mincheol Kang, Doru Kwon, Apeksha Parajulee, Junjeong Choi, Do Sik Min, Kuglae Kim, Wan Namkung, Yun-Hee Kim, Sang Myung Woo, Nam Doo Kim, Hee Chan Yoo and Jung Min Han ()
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Yulseung Sung: Yonsei University
Ya Chun Yu: Yonsei University
Mirim Lee: National Cancer Center
Seonghun Lim: Yonsei University
Yechan Lee: Yonsei University
Mincheol Kang: Yonsei University
Doru Kwon: Yonsei University
Apeksha Parajulee: Yonsei University
Junjeong Choi: Yonsei University
Do Sik Min: Yonsei University
Kuglae Kim: Yonsei University
Wan Namkung: Yonsei University
Yun-Hee Kim: National Cancer Center
Sang Myung Woo: National Cancer Center
Nam Doo Kim: CoBX Bio Inc.
Hee Chan Yoo: Chung-Ang University
Jung Min Han: Yonsei University

Nature Communications, 2025, vol. 16, issue 1, 1-25

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-64730-2

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