A Small Molecule Targeting the Transmembrane Domain of Death Receptor p75 NTR Induces Melanoma Cell Death and Reduces Tumor Growth

Cell Chem Biol. 2018 Dec 20;25(12):1485-1494.e5. doi: 10.1016/j.chembiol.2018.09.007. Epub 2018 Oct 4.

Abstract

Small molecules offer powerful ways to alter protein function. However, most proteins in the human proteome lack small-molecule probes, including the large class of non-catalytic transmembrane receptors, such as death receptors. We hypothesized that small molecules targeting the interfaces between transmembrane domains (TMDs) in receptor complexes may induce conformational changes that alter receptor function. Applying this concept in a screening assay, we identified a compound targeting the TMD of death receptor p75NTR that induced profound conformational changes and receptor activity. The compound triggered apoptotic cell death dependent on p75NTR and JNK activity in neurons and melanoma cells, and inhibited tumor growth in a melanoma mouse model. Due to their small size and crucial role in receptor activation, TMDs represent attractive targets for small-molecule manipulation of receptor function.

Keywords: AraTM; FRET; ToxCAT; cell death; chalcone; neurotrophin; screening.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Cell Death / drug effects
  • Cell Proliferation / drug effects
  • Dose-Response Relationship, Drug
  • Humans
  • Melanoma / drug therapy*
  • Melanoma / metabolism
  • Melanoma / pathology*
  • Mice
  • Molecular Structure
  • Neoplasms, Experimental / drug therapy
  • Neoplasms, Experimental / metabolism
  • Neoplasms, Experimental / pathology
  • Nerve Tissue Proteins / antagonists & inhibitors*
  • Nerve Tissue Proteins / metabolism
  • Neurons / drug effects
  • Neurons / metabolism
  • Receptors, Nerve Growth Factor / antagonists & inhibitors*
  • Receptors, Nerve Growth Factor / metabolism
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / pharmacology*
  • Structure-Activity Relationship

Substances

  • Antineoplastic Agents
  • NGFR protein, human
  • Nerve Tissue Proteins
  • Receptors, Nerve Growth Factor
  • Small Molecule Libraries