Impaired migration and lung invasion of human melanoma by a novel small molecule targeting the transmembrane domain of death receptor p75^NTR.

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

SUBMITTER: Lopes-Rodrigues V 

PROVIDER: S-EPMC12514245 | biostudies-literature | 2025 Oct

REPOSITORIES: biostudies-literature