Small Molecule Inhibitors of the Neuropilin-1 Vascular Endothelial Growth Factor A (VEGF-A) Interaction

Abstract

We report the molecular design and synthesis of EG00229, 2, the first small molecule ligand for the VEGF-A receptor neuropilin 1 (NRP1) and the structural characterization of NRP1−ligand complexes by NMR spectroscopy and X-ray crystallography. Mutagenesis studies localized VEGF-A binding in the NRP1 b1 domain and a peptide fragment of VEGF-A was shown to bind at the same site by NMR, providing the basis for small molecule design. Compound 2 demonstrated inhibition of VEGF-A binding to NRP1 and attenuated VEGFR2 phosphorylation in endothelial cells. Inhibition of migration of endothelial cells was also observed. The viability of A549 lung carcinoma cells was reduced by 2, and it increased the potency of the cytotoxic agents paclitaxel and 5-fluorouracil when given in combination. These studies provide the basis for design of specific small molecule inhibitors of ligand binding to NRP1.

A modified thymosin alpha 1 inhibits the growth of breast cancer both in vitro and in vivo: suppressment of cell proliferation, inducible cell apoptosis and enhancement of targeted anticancer effects

“…Then, the initial model was minimised using 2000 steepest descent steps and 2000 conjugate gradient steps under the CHARMmH force field. The final Ta1-CRGDK model, as a ligand, was docked with NRP-1 (PDB:3I97) [28] using the ZDOCK program [29], and the result was analysed using Molecular Operating Environment software.…”

Effect of C-Terminal Sequence on Competitive Semaphorin Binding to Neuropilin-1

“…Peptides 10; 11; 12 , peptidomimetics 13 , soluble receptor fragments 14 , and monoclonal antibodies 15; 16; 17 have all been explored as Nrp binding and blocking molecules. Peptides are the best-studied class of Nrp targeting and modulating molecules and have been developed not only for their competitive ligand binding activity but also for other diverse purposes including in vivo Nrp diagnostic imaging 18; 19 and for cargo targeting to Nrp-expressing tumors 20; 21 .…”

Neuropilin-1 is upregulated in hepatocellular carcinoma and contributes to tumour growth and vascular remodelling

“…In several studies, the up-regulation of NRP1 was correlated to the advanced stage of the disease [16][17][18] and the increase in the expression of both NRPs was associated with poor prognosis [19]. Conversely, targeting NRP1 with specific monoclonal antibodies [20], small interfering RNAs [21], soluble NRP1 [21][22][23][24], NRP1-inhibiting peptides [21,[25][26][27][28], and small molecular inhibitors of the NRP1/VEGF-A interaction [29] has been found to decrease tumour angiogenesis and growth.…”