MassIVE MSV000083740

Partial Public PXD013698

Metabolic Targeting of Cancer by a Ubiquinone Uncompetitive Inhibitor of Mitochondrial Complex I

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Description

SMIP004-7 is a small molecule inhibitor of mitochondrial respiration with selective in vivo anti-cancer activity through a yet unknown molecular target. We demonstrate here that SMIP004-7 targets drug-resistant cancer cells with stem-like features by inhibiting mitochondrial respiration complex I (NADH:ubiquinone oxidoreductase, CI). Instead of affecting the quinone binding site targeted by most CI inhibitors, SMIP004-7 and its cytochrome P450-dependent activated metabolite(s) have an uncompetitive mechanism of inhibition involving a distinct N-terminal region of catalytic subunit NDUFS2 that leads to rapid disassembly of CI. SMIP004-7 and an improved chemical analog selectively engage NDUFS2 in vivo to inhibit the growth of triple negative breast cancer transplants, a response mediated at least in part by boosting CD4+ and CD8+ T cell-mediated immune surveillance. Thus, SMIP004-7 defines an emerging class of ubiquinone uncompetitive CI inhibitors for cell autonomous and microenvironmental metabolic targeting of mitochondrial respiration in cancer. [doi:10.25345/C5G632] [dataset license: CC0 1.0 Universal (CC0 1.0)]

Keywords: Tandem Mass Tag (TMT) ; mitochondrial inhibitors ; Prostate cancer

Contact

Principal Investigators:
(in alphabetical order) 		Dieter Wolf, Xiamen University, China
Submitting User: alexcampos

Publications

Shashi Jain, Cheng Hu, Jerome Kluza, Wei Ke, Madalina Giurgiu, Andreas Bleilevens, Alexandre Rosa Campos, Adriana Charbono, Elmar Stickeler, Jochen Maurer, Elke Holinski-Feder, Angela Abicht, Arkadii Vaisburg, Guangcheng Luo, Philippe Marchetti, Yabin Cheng, Dieter A. Wolf.
Metabolic Targeting of Cancer by a Ubiquinone Uncompetitive Inhibitor of Mitochondrial Complex I.
(accepted Cell Chemical Biology).

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