RT Journal Article SR Electronic T1 Small, Nonpeptide p75NTR Ligands Induce Survival Signaling and Inhibit proNGF-Induced Death JF The Journal of Neuroscience JO J. Neurosci. FD Society for Neuroscience SP 5288 OP 5300 DO 10.1523/JNEUROSCI.3547-05.2006 VO 26 IS 20 A1 Stephen M. Massa A1 Youmei Xie A1 Tao Yang A1 Anthony W. Harrington A1 Mi Lyang Kim A1 Sung Ok Yoon A1 Rosemary Kraemer A1 Laura A. Moore A1 Barbara L. Hempstead A1 Frank M. Longo YR 2006 UL http://www.jneurosci.org/content/26/20/5288.abstract AB Studies showing that neurotrophin binding to p75NTR can promote cell survival in the absence of Trk (tropomyosin-related kinase) receptors, together with recent structural data indicating that NGF may bind to p75NTR in a monovalent manner, raise the possibility that small molecule p75NTR ligands that positively regulate survival might be found. A pharmacophore designed to capture selected structural and physical chemical features of a neurotrophin domain known to interact with p75NTR was applied to in silico screening of small molecule libraries. Small, nonpeptide, monomeric compounds were identified that interact with p75NTR. In cells showing trophic responses to neurotrophins, the compounds promoted survival signaling through p75NTR-dependent mechanisms. In cells susceptible to proneurotrophin-induced death, compounds did not induce apoptosis but inhibited proneurotrophin-mediated death. These studies identify a unique range of p75NTR behaviors that can result from isolated receptor liganding and establish several novel therapeutic leads.