title: ELR510444 inhibits tumor growth and angiogenesis by abrogating HIF activity and disrupting microtubules in renal cell carcinoma.
abstract: BACKGROUND
  Hypoxia-inducible factor (HIF) is an attractive therapeutic target for renal cell carcinoma (RCC) as its high expression due to the loss of von Hippel-Lindau (VHL) promotes RCC progression. Considering this, we hypothesized that ELR510444, a novel orally available small molecule inhibitor of HIF activity, would reduce angiogenesis and possess significant activity in RCC. The mechanism of action and therapeutic efficacy of ELR510444 were investigated in in vitro and in vivo models of RCC.
  
  
  RESULTS
  ELR510444 decreased HIF-1α and HIF-2α levels, reduced RCC cell viability and clonogenic survival, and induced apoptosis. VHL-deficient RCC cells were more sensitive to ELR510444-mediated apoptosis and restoration of VHL promoted drug resistance. Higher concentrations of ELR51044 promoted apoptosis independently of VHL status, possibly due to the microtubule destabilizing properties of this agent. ELR510444 significantly reduced tumor burden in the 786-O and A498 RCC xenograft models. These effects were associated with increased necrosis and apoptosis and inhibition of angiogenesis.
  
  
  CONCLUSIONS
  ELR510444 is a promising new HIF inhibitor that reduced RCC cell viability, induced apoptosis, and diminished tumor burden in RCC xenograft models. ELR510444 also destabilized microtubules suggesting that it possesses vascular disrupting and anti-angiogenic properties. Further investigation of ELR510444 for the therapy of RCC is warranted.
authors.affiliation: Department of Medicine and Institute for Drug Development, University of Texas Health Science Center, San Antonio, Texas, United States of America.
authors.forename: Jennifer S
authors.initials: JS
authors.lastname: Carew
authors.forename: Juan A
authors.initials: JA
authors.lastname: Esquivel
authors.forename: Claudia M
authors.initials: CM
authors.lastname: Espitia
authors.forename: Christoph M
authors.initials: CM
authors.lastname: Schultes
authors.forename: Marcel
authors.initials: M
authors.lastname: Mülbaier
authors.forename: Joe D
authors.initials: JD
authors.lastname: Lewis
authors.forename: Bernd
authors.initials: B
authors.lastname: Janssen
authors.forename: Francis J
authors.initials: FJ
authors.lastname: Giles
authors.forename: Steffan T
authors.initials: ST
authors.lastname: Nawrocki
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D051792:Basic Helix-Loop-Helix Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D002292:Carcinoma, Renal Cell / Q000098:blood supply / Q000378:metabolism / Q000473:pathology*; D015687:Cell Hypoxia / Q000187:drug effects; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors* / Q000235:genetics; D007680:Kidney Neoplasms / Q000098:blood supply / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008870:Microtubules / Q000187:drug effects* / Q000378:metabolism; D008938:Mitosis / Q000187:drug effects; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D058105:Polymerization / Q000187:drug effects; D013449:Sulfonamides / Q000494:pharmacology* / Q000627:therapeutic use; D013876:Thiophenes / Q000494:pharmacology* / Q000627:therapeutic use; D047368:Tumor Burden / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D000970:Antineoplastic Agents; D051792:Basic Helix-Loop-Helix Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D013449:Sulfonamides; D013876:Thiophenes; D042461:Vascular Endothelial Growth Factor A; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D000099162:Endothelial PAS Domain-Containing Protein 1; C557643:ELR 510444; C497442:HIF1A protein, human; C497446:VHL protein, human