Synthesis, Structural Elucidation, and Biological Evaluation of NSC12, an Orally Available Fibroblast Growth Factor (FGF) Ligand Trap for the Treatment of FGF-Dependent Lung Tumors

J Med Chem. 2016 May 26;59(10):4651-63. doi: 10.1021/acs.jmedchem.5b02021. Epub 2016 May 3.

Abstract

NSC12 is an orally available pan-FGF trap able to inhibit FGF2/FGFR interaction and endowed with promising antitumor activity. It was identified by virtual screening from a NCI small molecule library, but no data were available about its synthesis, stereochemistry, and physicochemical properties. We report here a synthetic route that allowed us to characterize and unambiguously identify the structure of the active compound by a combination of NMR spectroscopy and in silico conformational analysis. The synthetic protocol allowed us to sustain experiments aimed at assessing its therapeutic potential for the treatment of FGF-dependent lung cancers. A crucial step in the synthesis generated a couple of diastereoisomers, with only one able to act as a FGF trap molecule and to inhibit FGF-dependent receptor activation, cell proliferation, and tumor growth when tested in vitro and in vivo on murine and human lung cancer cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Animals
  • Antineoplastic Agents / administration & dosage
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Cell Proliferation / drug effects
  • Cholesterol / administration & dosage
  • Cholesterol / analogs & derivatives*
  • Cholesterol / chemistry
  • Cholesterol / pharmacology
  • Dose-Response Relationship, Drug
  • Drug Screening Assays, Antitumor
  • Fibroblast Growth Factors / antagonists & inhibitors*
  • Fibroblast Growth Factors / metabolism
  • Humans
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / pathology
  • Mice
  • Models, Molecular
  • Molecular Structure
  • Structure-Activity Relationship
  • Tumor Cells, Cultured

Substances

  • Antineoplastic Agents
  • NSC172285
  • Fibroblast Growth Factors
  • Cholesterol