complex i of oxidative phosphorylation

DX3-234 is a potent oxidative phosphorylation (OXPHOS) inhibitor that acts by inhibiting complex I in the mitochondrial electron transport chain (ETC), leading to intracellular ATP depletion and cell death, and can be used for the treatment of specific cancers dependent on aerobic metabolism, such as pancreatic cancer.

IACS-010759 is an orally bioavailable inhibitor of complex I of oxidative phosphorylation of the mitochondrial electron transport chain.

DX2-201 is a potent and selective inhibitor of oxidative phosphorylation (OXPHOS) complex I, with an IC50 of 312 nM, and it exhibits anticancer activity.

DX3-213B is a potent, orally active inhibitor of oxidative phosphorylation (OXPHOS) complex I with an IC50 of 3.6 nM. DX3-213B blocks ATP production (IC50: 11 nM) and inhibits the growth of MIA PaCa-2 cells (GI50: 11 nM). DX3-213B can be used to study pancreatic cancer.

TRAP1-IN-1 (compound 35) is a potent, selective TRAP1 inhibitor affecting the mitochondrial variant of Hsp90. It exhibits over 250-fold greater selectivity for TRAP1 compared to Grp94, destabilizes TRAP1 tetramers, and promotes the degradation of TRAP1 client proteins. Additionally, TRAP1-IN-1 impedes mitochondrial complex I activity involved in oxidative phosphorylation (OXPHOS), compromises the mitochondrial membrane potential, and augments glycolytic metabolism [1].

SCAL-255 is a mitochondrial complex I (CI) inhibitor, exhibiting potent inhibition with an IC50 of 1.14 μM. It impedes mitochondrial function by blocking oxygen consumption rate (OCR), inducing reactive oxygen species (ROS) production, and diminishing mitochondrial membrane potential (MMP). Furthermore, SCAL-255 significantly hampers the proliferation of cancer cells reliant on oxidative phosphorylation (OXPHOS) [1].

SCAL-266, a potent inhibitor of mitochondrial complex I (CI), exhibits an IC50 of 0.83 μM. This compound impairs mitochondrial function by blocking oxidative phosphorylation (OXPHOS), inhibiting oxygen consumption rate (OCR), increasing reactive oxygen species (ROS) production, and diminishing mitochondrial membrane potential (MMP). Furthermore, SCAL-266 demonstrates significant antiproliferative activity against OXPHOS-dependent cancer cells [1].

HP661, a selective inhibitor of mitochondrial complex I (NADH dehydrogenase), impedes complex I activity by 77.6% at 1 µM, demonstrating lesser inhibition towards complex III (28.1%) and no inhibitory effects on complexes II and IV. It notably decreases the viability of human lung cancer cells—H460, NCI H441, and trametinib-resistant A549 cells (IC50s = 10.6, 29.7, and 15.1 nM, respectively)—which exhibit high levels of oxidative phosphorylation. In contrast, it shows minimal activity against NCI H358 lung cancer cells and non-cancerous HPNE and MRC-5 cells (IC50s = >10,000 nM for both), which have lower oxidative phosphorylation levels. Furthermore, in an H460 mouse xenograft model, HP661 at a dose of 30 mg/kg twice daily significantly reduces tumor volume and enhances the tumor-growth inhibitory effects of trametinib.