2. Academic Validation
  3. Targeting cancer glutamine dependency with a first-in-class inhibitor of the mitochondrial glutamine transporter SLC1A5_var

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

  • Nat Commun. 2025 Nov 3;16(1):9690. doi: 10.1038/s41467-025-64730-2.
Yulseung Sung 1,  Ya Chun Yu 1,  Mirim Lee 2,  Seonghun Lim 1,  Yechan Lee 1,  Mincheol Kang 1,  Doru Kwon 1,  Apeksha Parajulee 1,  Junjeong Choi 1,  Do Sik Min 1,  Kuglae Kim 1,  Wan Namkung 1,  Yun-Hee Kim 2,  Sang Myung Woo 2 3,  Nam Doo Kim 4,  Hee Chan Yoo 5,  Jung Min Han 6 7
Affiliations

Affiliations

  • 1 Yonsei Institute of Pharmaceutical Sciences, College of Pharmacy, Yonsei University, Incheon, 21983, Republic of Korea.
  • 2 Research Institute, National Cancer Center, Goyang, 10408, Republic of Korea.
  • 3 Center for Liver and Pancreatobiliary Cancer, Hospital, National Cancer Center, Goyang, 10408, Republic of Korea.
  • 4 CoBX Bio Inc., 21 Yangji-ro, Gwangmyeong-si, Gyeonggi-do, 14345, Republic of Korea.
  • 5 College of Pharmacy, Chung-Ang University, Seoul, 06974, Republic of Korea.
  • 6 Yonsei Institute of Pharmaceutical Sciences, College of Pharmacy, Yonsei University, Incheon, 21983, Republic of Korea. jhan74@yonsei.ac.kr.
  • 7 POSTECH Biotech Center, Pohang University of Science and Technology, Pohang, 37673, Republic of Korea. jhan74@yonsei.ac.kr.
PMID: 41184297 DOI: 10.1038/s41467-025-64730-2
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.

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