Small, Nonpeptide p75NTRLigands Induce Survival Signaling and Inhibit proNGF-Induced Death

• DOI: 10.1523/jneurosci.3547-05.2006
• Publication Date: 2006-05-18T00:19:27Z
• Authors: Stephen M. Massa; Youmei Xie; Tao Yang; Anthony W. Harrin...; Mi Lyang Kim; Sung Ok Yoon; Rosemary Kraemer; Laura A. Moore; Barbara L. Hempstead; Frank M. Longo
• Keywords: Trk receptor

Studies showing that neurotrophin binding to p75 NTR can promote cell survival in the absence of Trk (tropomyosin-related kinase) receptors, together with recent structural data indicating NGF may bind a monovalent manner, raise possibility small molecule ligands positively regulate might be found. A pharmacophore designed capture selected and physical chemical features domain known interact was applied silico screening libraries. Small, nonpeptide, monomeric compounds were identified . In cells trophic responses neurotrophins, promoted signaling through -dependent mechanisms. susceptible proneurotrophin-induced death, did not induce apoptosis but inhibited proneurotrophin-mediated death. These studies identify unique range behaviors result from isolated receptor liganding establish several novel therapeutic leads.