Alofanib, an allosteric FGFR2 inhibitor, has potent effects on ovarian cancer growth in preclinical studies.

Purpose Early data suggest that combining FGFR2 inhibitors with platinum-containing cytotoxic agents for the treatment of epithelial ovarian cancer may yield increased antitumor activity. We investigated antitumor activity of alofanib (RPT835), a novel allosteric FGFR2 inhibitor, in ovarian cancer in vitro and in vivo. Methods Equal amounts of ovarian cancer cell (SKOV3) lysates were analyzed for FGFR1-3 protein expression using Wes.

Molecular Modeling, de novo Design and Synthesis of a Novel, Extracellular Binding Fibroblast Growth Factor Receptor 2 Inhibitor Alofanib (RPT835).

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.

Structure-activity relationships in cholapod anion carriers: enhanced transmembrane chloride transport through substituent tuning.

Chloride transport by a series of steroid-based "cholapod" receptors/carriers was studied in vesicles. The principal method involved preincorporation of the cholapods in the vesicle membranes, and the use of lucigenin fluorescence quenching to detect inward-transported Cl-. The results showed a partial correlation between anion affinity and transport activity, in that changes at the steroidal 7 and 12 positions affected both properties in concert.

The "triamino-analogue" of methyl allocholate; a rigid, functionalised scaffold for supramolecular chemistry.

Cholic acid has been converted into triamine with the all-trans polycyclic allocholanoyl skeleton and co-directed, axial amino groups; the potential of this system as a scaffold is illustrated by conversion to a preorganised anion receptor.

Substrate discrimination by cholapod anion receptors: geometric effects and the "affinity-selectivity principle".

Cholapod anion receptors can achieve high affinities while maintaining compatibility with nonpolar media. Previously they have been shown to transport anions across cell and vesicle membranes. In the present work, the scope of the architecture is expanded and structure-selectivity relationships are investigated.

A fluorescent assay for chloride transport; identification of a synthetic anionophore with improved activity.

A fluorescent assay based on the chloride-sensitive probe, lucigenin, is developed for monitoring chloride transport into vesicles, and used to compare the effectiveness of three steroid-derived transporters.

Electrochemical quantification of high-affinity halide binding by a steroid-based receptor.

The strength of binding between a cholapod receptor and halide anions is quantified using voltammetry at the liquid/liquid interface, revealing very high affinities and size-selectivity peaking at chloride.