title: BAY 87-2243, a highly potent and selective inhibitor of hypoxia-induced gene activation has antitumor activities by inhibition of mitochondrial complex I.
abstract: 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-1α and HIF-2α protein accumulation under hypoxic conditions in non-small cell lung cancer (NSCLC) cell line H460 but had no effect on HIF-1α 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-1α 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.
authors.affiliation: Bayer Pharma AG, Global Drug Discovery, Wuppertal, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Ellinghaus
authors.forename: Iring
authors.initials: I
authors.lastname: Heisler
authors.forename: Kerstin
authors.initials: K
authors.lastname: Unterschemmann
authors.forename: Michael
authors.initials: M
authors.lastname: Haerter
authors.forename: Hartmut
authors.initials: H
authors.lastname: Beck
authors.forename: Susanne
authors.initials: S
authors.lastname: Greschat
authors.forename: Alexander
authors.initials: A
authors.lastname: Ehrmann
authors.forename: Holger
authors.initials: H
authors.lastname: Summer
authors.forename: Ingo
authors.initials: I
authors.lastname: Flamme
authors.forename: Felix
authors.initials: F
authors.lastname: Oehme
authors.forename: Karlheinz
authors.initials: K
authors.lastname: Thierauch
authors.forename: Martin
authors.initials: M
authors.lastname: Michels
authors.forename: Holger
authors.initials: H
authors.lastname: Hess-Stumpp
authors.forename: Karl
authors.initials: K
authors.lastname: Ziegelbauer
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000096:biosynthesis / Q000235:genetics; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases / Q000096:biosynthesis / Q000235:genetics; D015687:Cell Hypoxia / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery / Q000379:methods; D042967:Electron Transport Complex I / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D052138:Genes, Neoplasm; D017930:Genes, Reporter; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000096:biosynthesis / Q000235:genetics; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases / Q000235:genetics / Q000378:metabolism; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D008969:Molecular Sequence Data; D058990:Molecular Targeted Therapy / Q000379:methods; D010069:Oxadiazoles / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology* / Q000627:therapeutic use; D011720:Pyrazoles / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology* / Q000627:therapeutic use; D034741:RNA, Small Interfering / Q000235:genetics; D054852:Small Molecule Libraries; D047368:Tumor Burden / Q000187:drug effects; D014407:Tumor Cells, Cultured; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000502:physiology; D023041:Xenograft Model Antitumor Assays / Q000379:methods
chemical_list: C000591541:1-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; D000951:Antigens, Neoplasm; D051793:Hypoxia-Inducible Factor 1; D010069:Oxadiazoles; D011720:Pyrazoles; D034741:RNA, Small Interfering; D054852:Small Molecule Libraries; C490190:EGLN1 protein, human; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C089226:CA9 protein, human; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases; C497446:VHL protein, human; D042967:Electron Transport Complex I
keywords: Antitumor activity; hypoxia; hypoxia-inducible factor-1; mitochondrial complex 1