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.

CONCLUSION:

These results provide strong rationale for the evaluation of compound in advanced cancers.

• Authors: Ilya Tsimafeyeu, Frits Daeyaert, Jean-Baptiste Joos, Koen V Aken, John Ludes-Meyers, Mikhail Byakhov, Sergei Tjulandin
• Journal: Medicinal chemistry (Shariqah (United Arab Emirates)) (Med Chem) Vol. 12 Issue 4 Pg. 303-17 ( 2016) ISSN: 1875-6638 [Electronic] Netherlands
• PMID: 26732115 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• Benzoates
• Sulfonamides
• Receptor, Fibroblast Growth Factor, Type 2
• alofanib

Topics

• Allosteric Regulation
• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Benzoates (chemical synthesis, chemistry, pharmacology)
• Cell Line, Tumor
• Drug Screening Assays, Antitumor
• Humans
• Models, Chemical
• Molecular Docking Simulation
• Receptor, Fibroblast Growth Factor, Type 2 (antagonists & inhibitors)
• Structure-Activity Relationship
• Sulfonamides (chemical synthesis, chemistry, pharmacology)