title: Molecular Modeling, de novo Design and Synthesis of a Novel, Extracellular Binding Fibroblast Growth Factor Receptor 2 Inhibitor Alofanib (RPT835).
abstract: BACKGROUND
  Fibroblast growth factor (FGF) receptors (FGFRs) play a key role in tumor growth and angiogenesis. The present report describes our search for an extracellularly binding FGFR inhibitor using a combined molecular modeling and de novo design strategy.
  
  
  METHODS
  Based upon crystal structures of the receptor with its native ligand and knowledge of inhibiting peptides, we have developed a computational protocol that predicts the putative binding of a molecule to the extracellular domains of the receptor. This protocol, or scoring function, was used in combination with the de novo synthesis program 'SYNOPSIS' to generate high scoring and synthetically accessible compounds.
  
  
  RESULTS
  Eight compounds belonging to 3 separate chemical classes were synthesized. One of these compounds, alofanib (RPT835), was found to be an effective inhibitor of the FGF/FGFR2 pathway. The preclinical in vitro data support an allosteric inhibition mechanism of RPT835. RPT835 potently inhibited growth of KATO III gastric cancer cells expressing FGFR2, with GI50 value of 10 nmol/L.
  
  
  CONCLUSIONS
  These results provide strong rationale for the evaluation of compound in advanced cancers.
authors.affiliation: Ruspharmtech LLC, Griboyedov canal nab. 130 Liter A, off. 202, Saint Petersburg, 190121, Russia. tsimafeyeu@ruspharm.com.
authors.forename: Ilya
authors.initials: I
authors.lastname: Tsimafeyeu
authors.forename: Frits
authors.initials: F
authors.lastname: Daeyaert
authors.forename: Jean-Baptiste
authors.initials: JB
authors.lastname: Joos
authors.forename: Koen V
authors.initials: KV
authors.lastname: Aken
authors.forename: John
authors.initials: J
authors.lastname: Ludes-Meyers
authors.forename: Mikhail
authors.initials: M
authors.lastname: Byakhov
authors.forename: Sergei
authors.initials: S
authors.lastname: Tjulandin
mesh_terms: D000494:Allosteric Regulation; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D001565:Benzoates / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008956:Models, Chemical; D062105:Molecular Docking Simulation; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D001565:Benzoates; D013449:Sulfonamides; D051497:Receptor, Fibroblast Growth Factor, Type 2; C000610985:alofanib