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