PMID- 24403227 OWN - NLM STAT- MEDLINE DCOM- 20140916 LR - 20220409 IS - 2045-7634 (Electronic) IS - 2045-7634 (Print) IS - 2045-7634 (Linking) VI - 2 IP - 5 DP - 2013 Oct TI - BAY 87-2243, a highly potent and selective inhibitor of hypoxia-induced gene activation has antitumor activities by inhibition of mitochondrial complex I. PG - 611-24 LID - 10.1002/cam4.112 [doi] AB - The activation of the transcription factor hypoxia-inducible factor-1 (HIF-1) plays an essential role in tumor development, tumor progression, and resistance to chemo- and radiotherapy. In order to identify compounds targeting the HIF pathway, a small molecule library was screened using a luciferase-driven HIF-1 reporter cell line under hypoxia. The high-throughput screening led to the identification of a class of aminoalkyl-substituted compounds that inhibited hypoxia-induced HIF-1 target gene expression in human lung cancer cell lines at low nanomolar concentrations. Lead structure BAY 87-2243 was found to inhibit HIF-1alpha and HIF-2alpha protein accumulation under hypoxic conditions in non-small cell lung cancer (NSCLC) cell line H460 but had no effect on HIF-1alpha protein levels induced by the hypoxia mimetics desferrioxamine or cobalt chloride. BAY 87-2243 had no effect on HIF target gene expression levels in RCC4 cells lacking Von Hippel-Lindau (VHL) activity nor did the compound affect the activity of HIF prolyl hydroxylase-2. Antitumor activity of BAY 87-2243, suppression of HIF-1alpha protein levels, and reduction of HIF-1 target gene expression in vivo were demonstrated in a H460 xenograft model. BAY 87-2243 did not inhibit cell proliferation under standard conditions. However under glucose depletion, a condition favoring mitochondrial ATP generation as energy source, BAY 87-2243 inhibited cell proliferation in the nanomolar range. Further experiments revealed that BAY 87-2243 inhibits mitochondrial complex I activity but has no effect on complex III activity. Interference with mitochondrial function to reduce hypoxia-induced HIF-1 activity in tumors might be an interesting therapeutic approach to overcome chemo- and radiotherapy-resistance of hypoxic tumors. CI - (c) 2013 The Authors. Cancer Medicine published by John Wiley & Sons Ltd. FAU - Ellinghaus, Peter AU - Ellinghaus P AD - Bayer Pharma AG, Global Drug Discovery, Wuppertal, Germany. FAU - Heisler, Iring AU - Heisler I FAU - Unterschemmann, Kerstin AU - Unterschemmann K FAU - Haerter, Michael AU - Haerter M FAU - Beck, Hartmut AU - Beck H FAU - Greschat, Susanne AU - Greschat S FAU - Ehrmann, Alexander AU - Ehrmann A FAU - Summer, Holger AU - Summer H FAU - Flamme, Ingo AU - Flamme I FAU - Oehme, Felix AU - Oehme F FAU - Thierauch, Karlheinz AU - Thierauch K FAU - Michels, Martin AU - Michels M FAU - Hess-Stumpp, Holger AU - Hess-Stumpp H FAU - Ziegelbauer, Karl AU - Ziegelbauer K LA - eng SI - GENBANK/GSE42791 PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20130820 PL - United States TA - Cancer Med JT - Cancer medicine JID - 101595310 RN - 0 (1-cyclopropyl-4-(4-((5-methyl-3-(3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)-1H-pyrazol-1-yl)methyl)pyridin-2-yl)piperazine) RN - 0 (Antigens, Neoplasm) RN - 0 (Hypoxia-Inducible Factor 1) RN - 0 (Oxadiazoles) RN - 0 (Pyrazoles) RN - 0 (RNA, Small Interfering) RN - 0 (Small Molecule Libraries) RN - EC 1.14.11.2 (EGLN1 protein, human) RN - EC 1.14.11.29 (Hypoxia-Inducible Factor-Proline Dioxygenases) RN - EC 2.3.2.27 (Von Hippel-Lindau Tumor Suppressor Protein) RN - EC 4.2.1.1 (CA9 protein, human) RN - EC 4.2.1.1 (Carbonic Anhydrase IX) RN - EC 4.2.1.1 (Carbonic Anhydrases) RN - EC 6.3.2.- (VHL protein, human) RN - EC 7.1.1.2 (Electron Transport Complex I) SB - IM MH - Animals MH - Antigens, Neoplasm/biosynthesis/genetics MH - Carbonic Anhydrase IX MH - Carbonic Anhydrases/biosynthesis/genetics MH - Cell Hypoxia/genetics MH - Cell Proliferation/drug effects MH - Dose-Response Relationship, Drug MH - Drug Discovery/methods MH - Electron Transport Complex I/*antagonists & inhibitors/metabolism MH - Female MH - Gene Expression Regulation, Neoplastic/drug effects MH - Genes, Neoplasm MH - Genes, Reporter MH - Humans MH - Hypoxia-Inducible Factor 1/biosynthesis/genetics MH - Hypoxia-Inducible Factor-Proline Dioxygenases/genetics/metabolism MH - Lung Neoplasms/drug therapy/genetics/*metabolism/pathology MH - Mice MH - Mice, Nude MH - Molecular Sequence Data MH - Molecular Targeted Therapy/methods MH - Oxadiazoles/administration & dosage/blood/*pharmacology/therapeutic use MH - Pyrazoles/administration & dosage/blood/*pharmacology/therapeutic use MH - RNA, Small Interfering/genetics MH - Small Molecule Libraries MH - Tumor Burden/drug effects MH - Tumor Cells, Cultured MH - Von Hippel-Lindau Tumor Suppressor Protein/physiology MH - Xenograft Model Antitumor Assays/methods PMC - PMC3892793 OTO - NOTNLM OT - Antitumor activity OT - hypoxia OT - hypoxia-inducible factor-1 OT - mitochondrial complex 1 EDAT- 2014/01/10 06:00 MHDA- 2014/09/17 06:00 PMCR- 2013/10/01 CRDT- 2014/01/10 06:00 PHST- 2013/04/18 00:00 [received] PHST- 2013/05/27 00:00 [revised] PHST- 2013/07/05 00:00 [accepted] PHST- 2014/01/10 06:00 [entrez] PHST- 2014/01/10 06:00 [pubmed] PHST- 2014/09/17 06:00 [medline] PHST- 2013/10/01 00:00 [pmc-release] AID - 10.1002/cam4.112 [doi] PST - ppublish SO - Cancer Med. 2013 Oct;2(5):611-24. doi: 10.1002/cam4.112. Epub 2013 Aug 20.