Metabolic targeting of cancer by a ubiquinone uncompetitive inhibitor of mitochondrial complex I

Jain, Shashi; Hu, Cheng; Kluza, Jerome; Ke, Wei; Tian, Guiyou; Giurgiu, Madalina; Bleilevens, Andreas; Campos, Alexandre Rosa; Charbono, Adriana; Stickeler, Elmar; Maurer, Jochen; Holinski-Feder, Elke; Vaisburg, Arkadii; Bureik, Matthias; Luo, Guangcheng; Marchetti, Philippe; Cheng, Yabin und Wolf, Dieter A. (2022): Metabolic targeting of cancer by a ubiquinone uncompetitive inhibitor of mitochondrial complex I. In: Cell Chemical Biology, Bd. 29, Nr. 3, E15: S. 436-450

Abstract

SMIP004-7 is a small molecule inhibitor of mitochondrial respiration with selective in vivo anti-cancer activity through an as-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, complex I [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.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 2451-9456
• Sprache: Englisch