2025/09/17 by Vanessa Lopes-Rodrigues, Samuel Agyei Nyantakyi, Xueqing Lun +12 · 1 voice
Biochemistry, Genetics and Molecular Biology · Medicine · #Cell Adhesion Molecules Research #Melanoma and MAPK Pathways #Receptor Mechanisms and Signaling
paper · doi:10.1038/s44321-025-00297-1
openalex publication_date 2025/09/17 · openalex created_date 2025/10/10 · openalex updated_date 2026/08/01
Abstract Receptor transmembrane domains (TMDs) are crucially involved in relaying ligand information from extracellular to intracellular spaces and represent attractive targets for small molecule manipulation of receptor function. Screening a library of over 8000 drug-like compounds with an assay based on the TMD of death receptor p75 NTR , we identified a novel small molecule capable of inhibiting p75 NTR -mediated migration of human melanoma cells. Employing medicinal chemistry, a more potent derivative termed Np75-4A22 was identified that blocked nerve growth factor (NGF)-mediated melanoma invasion at sub-micromolar concentrations. The specific interaction of Np75-4A22 with the p75 NTR TMD was confirmed by 2D NMR. Mechanistically, Np75-4A22 was found to antagonize NGF-mediated recruitment of the actin-bundling protein fascin to p75 NTR , fascin association with the actin cytoskeleton and filopodia formation. Importantly, preclinical assessment of Np75-4A22 showed high oral bioavailability, low toxicity, and significant inhibition of melanoma lung invasion in mice. These results support further development of this approach as an alternative or complementary strategy for melanoma cancer patients that do not respond to conventional chemotherapy or immune checkpoint inhibitors.