Protein-Protein Interaction (PPI) Target - Drug Discovery Case Study

January, 2012

Ark Therapeutics and Domainex worked together to develop what are believed to be the first small molecule antagonists with nanomolar potencies for the neuropilin 1 (NRP1) receptor. This is considered to be a protein-protein interaction target of high potential in the treatment of cancer.

NRP1 is a receptor for vascular endothelial growth factor A165 (VEGF-A165) and the neuronal guidance molecule semaphorin 3A (SEMA3A)2 with key roles in vascular and neuronal development. In endothelial cells, NRP1 enhances the biological signals of VEGF-A mediated by binding to its receptor vascular endothelial growth factor 2 (VEGFR2).

NRP1 has also been implicated in tumour growth and angiogenesis.  Inhibition by a blocking antibody that prevents VEGF-A binding to NRP1, enhanced the antitumor effects of the inhibitory anti-VEGF-A antibody, bevacizumab in mouse xenograft models.  It is therefore believed that a small molecule inhibitor of NRP1 function would be desirable, but inhibitors of protein-protein interactions are not trivial to develop.

Domainex and Ark worked together successfully to develop inhibitors of this interaction, using a peptidomimetic approach. This work was published by Jarvis et al. in 2010 and Haiyan Jia et al. in 2014.