1227158-85-1

BAY 87-2243 (1227158-85-1) potently inhibits HIF-1 reporter gene activity (IC50?= 0.7 nM) and CA9 protein expression (IC50?= 2.0 nM).1?It inhibited HIF-1α and HIF-2α protein accumulation in hypoxic H460 cells and reduced tumor weight in nude mice inoculated with H460 cells. BAY 87-2243 potently inhibits mitochondrial complex I activity (IC50?= 10 nM in mitochondria isolated from PC3 cells) leading to its HIF-1 effects. It has no effect on mitochondrial complex III. BAY 87-2243 reduced melanoma tumor growth?via?its targeting of mitochondrial complex I.2,3

BAY 87-2243 is a highly potent and selective inhibitor of hypoxia-induced gene activation. It is found to inhibit HIF-1α and HIF-2α protein accumulation under hypoxic conditions in non-small cell lung cancer cell line H460. It inhibits mitochondrial complex I activity and therefore may be used in antitumor treatment to overcome chemo- and radiotherapy- resistance of hypoxic tumors.

This Hif1a inhibitor (FW = 525.53 g/mol; CAS 1227158-85-1; Solubility: <1 mg/mL DMSO or H2O) targets the transcription factor hypoxia-inducible factor-1 (HIF-1), which plays an essential role in tumor development, tumor progression, and resistance to chemo- and radiotherapy. BAY 87-2243 inhibits HIF-1α and HIF-2α accumulation under hypoxic conditions in the H460 Non-Small Cell Lung Cancer (NSCLC) cell line but is without effect on HIF-1α protein levels that are induced by such hypoxia mimetics asdesferrioxamine or cobalt chloride. BAY 87-2243 has no effect on HIF target gene expression levels in RCC4 cells lacking Von Hippel-Lindau (VHL) activity; nor does it affect the activity of HIF prolyl hydroxylase-2. Antitumor activity of BAY 87-2243, suppression of HIF-1α protein levels, and reduction of HIF-1 target gene expression in vivo have been demonstrated in a H460 xenograft model. BAY 87-2243 does not inhibit cell proliferation under standard conditions. Upon glucose depletion, a condition favoring mitochondrial ATP generation as energy source, BAY 87-2243 inhibits cell proliferation in the low-nM range. In a mouse model for BRAF- mutant melanoma, BAY 87-2243-mediated complex I inhibition induces melanoma cell death in vitro and reduces melanoma tumor growth in various mouse models in vivo. This effect is mediated through BAY 87-2243- induced stimulation of mitochondrial ROS production, leading to oxidative damage and subsequent cell death. BAY 87-2243 displays increased anti- tumor efficacy compared to single agent treatment, when combined with the BRAF inhibitor vemurafenib in nude mice with BRAF mutant melanoma xenografts.

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1) Ellinghaus?et al.?(2013),?BAY 87-2243, a highly potent and selective inhibitor of hypoxia-induced gene activation has antitumor activities by inhibition of mitochondrial complex I; Cancer Med.,2?611 2) Schockel?et al.?(2015),?Targeting mitochondrial complex I using BAY 87-2243 reduces melanoma tumor growth; Cancer Metab.,?3?11 3) Basit?et al.?(2017),?Mitochondrial complex I inhibition triggers a mitophagy-dependent ROS increase leading to necroptosis and ferroptosis in melanoma cells; Cell Death Discov.,?8?e2716