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Nat. Commun., 03 November 2025;16, 9690(2025) | https://doi.org/10.1038/s41467-025-64730-2
Targeting cancer glutamine dependency with a first-in-class inhibitor of the mitochondrial glutamine transporter SLC1A5_var
Yulseung Sung1, Ya Chun Yu1, Mirim Lee2, Seonghun Lim1, Yechan Lee1, Mincheol Kang1, Doru Kwon1, Apeksha Parajulee1, Junjeong Choi1, Do Sik Min1, Kuglae Kim1, Wan Namkung1, Yun-Hee Kim2, Sang Myung Woo2,3, Nam Doo Kim4, Hee Chan Yoo5 & Jung Min Han1,6
1Yonsei Institute of Pharmaceutical Sciences, College of Pharmacy,Yonsei University, Incheon 21983, Republic of Korea.
2ResearchInstitute, National Cancer Center, Goyang 10408, Republic of Korea.
3Center for Liver and Pancreatobiliary Cancer, Hospital, National Cancer Center, Goyang 10408, Republic of Korea.
4CoBX Bio Inc., 21 Yangji-ro, Gwangmyeong-si, Gyeonggi-do 14345, Republic of Korea.
5College of Pharmacy, Chung-Ang University, Seoul 06974, Republic of Korea.
6POSTECH Biotech Center, Pohang University of Science and Technology, Pohang 37673, Republic of Korea.
Corresponding author
Correspondence to Jung Min Han.
1Yonsei Institute of Pharmaceutical Sciences, College of Pharmacy,Yonsei University, Incheon 21983, Republic of Korea.
2ResearchInstitute, National Cancer Center, Goyang 10408, Republic of Korea.
3Center for Liver and Pancreatobiliary Cancer, Hospital, National Cancer Center, Goyang 10408, Republic of Korea.
4CoBX Bio Inc., 21 Yangji-ro, Gwangmyeong-si, Gyeonggi-do 14345, Republic of Korea.
5College of Pharmacy, Chung-Ang University, Seoul 06974, Republic of Korea.
6POSTECH Biotech Center, Pohang University of Science and Technology, Pohang 37673, Republic of Korea.
Corresponding author
Correspondence to Jung Min Han.
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.
논문정보
- Research article
- 2025년 11월 (BRIC 등록일 2025-11-04)
- 국내 연구진
- 의약학 > 약학
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