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This galley proof is being listed electronically before publishing the final manuscript (It's not final version).

Selective cytotoxicity of a novel mitochondrial complex I inhibitor, YK-135, against EMT-subtype gastric cancer cell lines due to impaired glycolytic capacity
Yeojin Sung1,# (Graduate student), Seungbin Cha1,# (Post doctoral fellow), Sang Bum Kim1 (Research professor), Hakhyun Kim1 (Graduate student), Seonghwi Choi3 (Graduate student), Sejin Oh1 (Graduate student), Minseo Kim1 (Research worker), Yunji Lee1,2 (Graduate student), Gino Kwon4 (Graduate student), Jooyoung Lee1,5 (Research professor), Joo-Youn Lee6 (Researcher), Gyoonhee Han3,7 (Professor), Hyun Seok Kim 1,2,5,* (Associate professor)
1Severance Biomedical Science Institute and 2Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul 03722, Republic of Korea,
3Department of Integrated OMICS for Biomedical Sciences (WCU Program) and 4Graduate Program for Nanomedical Science, Yonsei University, Seoul 03722, Republic of Korea,
5Checkmate Therapeutics Inc., Yeongdeungpo-gu, Seoul 07207, Republic of Korea,
6Therapeutics and Biotechnology Division, Korea Research Institute of Chemical Technology, 141 Gajeong-ro, Jang-dong, Yuseong-gu, Daejeon 34114, Republic of Korea,
7Department of Biotechnology, Yonsei University, Seoul 03722, Republic of Korea
Epithelial-to-mesenchymal transition (EMT)-subtype gastric cancers have the worst prognosis due to their higher recurrence rate, higher probability of developing metastases and higher chemo-resistance compared to those of other molecular subtypes. Pharmacologically actionable somatic mutations are rarely found in EMT-subtype gastric cancers, limiting the utility of targeted therapies. Here, we conducted a high-throughput chemical screen using 37 gastric cancer cell lines and 48,467 synthetic small-molecule compounds. We identified YK-135, a small-molecule compound that showed higher cytotoxicity toward EMT-subtype gastric cancer cell lines than toward non-EMT-subtype gastric cancer cell lines. YK-135 exerts its cytotoxic effects by inhibiting mitochondrial complex I activity and inducing AMP-activated protein kinase (AMPK)-mediated apoptosis. We found that the lower glycolytic capacity of the EMT-subtype gastric cancer cells confers synthetic lethality to the inhibition of mitochondrial complex I, possibly by failing to maintain energy homeostasis. Other well-known mitochondrial complex I inhibitors (e.g., rotenone and phenformin) mimic the efficacy of YK-135, supporting our results. These findings highlight mitochondrial complex I inhibitors as promising therapeutic agents for EMT-subtype gastric cancers and YK-135 as a novel chemical scaffold for further drug development.
Abstract, Accepted Manuscript(in press) [Submitted on September 26, 2022, Accepted on November 14, 2022]
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