The Neuropilin (Nrp) family of cell surface receptors have key physiological and pathological functions. Nrp2 is of particular interest due to its involvement in tumor metastasis. Currently, peptide and small molecule inhibitors that target Nrp utilize arginine-based molecules which have limitations due to high inherent flexibility and issues related to stability. Further, there are no known small molecule inhibitors specific for Nrp2. Recent molecular insights identify a key ligand binding region in the b1 domain of Nrp2 responsible for binding the C-terminus of its cognate ligand VEGF-C. Based on this, we report the discovery of a novel benzamidine-based inhibitor that functions through competitive inhibition of VEGF-C binding to Nrp2. Further, we have explored inhibitor functionality and selectivity by defining its structure–activity relationship (SAR) providing valuable insights on this benzamidine-based family of Nrp2 inhibitors. This study provides the basis for further development of a potent and specific small molecule inhibitor that competitively targets pathological Nrp2 function.
|Published - Jul 2020
Bibliographical noteFunding Information:
We thank members of the Vander Kooi laboratory for helpful discussions and comments. In addition, we thank Prof. David Hangauer for his support. This work was supported by National Institutes of Health grant R01GM094155 (C.W.V.K.).
© 2020 Elsevier Inc.
ASJC Scopus subject areas
- Molecular Biology
- Drug Discovery
- Organic Chemistry