6533b7d5fe1ef96bd1265128

RESEARCH PRODUCT

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

Marco MorRiccardo CastelliNicole BozzaArianna GiacominiMarco PrestaSara MatarazzoMattia AnselmiRoberto RoncaFederica VacondioSilvia Rivara

subject

Models Molecular0301 basic medicineLung NeoplasmssynthesisFGF Lung cancer growth factor chemical characterization synthesisIn silicoAdministration OralAntineoplastic AgentsPharmacologyFibroblast growth factorMiceStructure-Activity Relationship03 medical and health sciences0302 clinical medicineIn vivoDrug DiscoveryTumor Cells CulturedAnimalsHumansFGFStructure–activity relationshipCell ProliferationDose-Response Relationship DrugMolecular Structurechemical characterizationCell growthChemistrygrowth factorLigand (biochemistry)Small moleculeCell biologyFibroblast Growth FactorsCholesterol030104 developmental biologyFibroblast growth factor receptor030220 oncology & carcinogenesisMolecular MedicineDrug Screening Assays AntitumorLung cancer

description

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.

yearjournalcountryeditionlanguage
2016-01-01Journal of Medicinal Chemistry
https://doi.org/10.1021/acs.jmedchem.5b02021