2. Academic Validation
  3. A Small Molecule Targeting the Transmembrane Domain of Death Receptor p75NTR Induces Melanoma Cell Death and Reduces Tumor Growth

A Small Molecule Targeting the Transmembrane Domain of Death Receptor p75NTR 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.
Eddy T H Goh 1,  Zhi Lin 2,  Bo Young Ahn 3,  Vanessa Lopes-Rodrigues 2,  Ngoc Ha Dang 3,  Shuhailah Salim 2,  Bryan Berger 4,  Brian Dymock 5,  Donna L Senger 3,  Carlos F Ibáñez 6
Affiliations

Affiliations

  • 1 Department of Physiology, National University of Singapore, Singapore 117597, Singapore; Life Sciences Institute, National University of Singapore, Singapore 117456, Singapore; Department of Cell and Molecular Biology, Karolinska Institute, Stockholm 17165, Sweden.
  • 2 Department of Physiology, National University of Singapore, Singapore 117597, Singapore; Life Sciences Institute, National University of Singapore, Singapore 117456, Singapore.
  • 3 Arnie Charbonneau Cancer Institute, Department of Oncology, Cumming School of Medicine, University of Calgary, Calgary T2N 1N4, Canada.
  • 4 Department of Chemical Engineering, University of Virginia, Charlottesville, VA 22904, USA.
  • 5 Department of Pharmacy, National University of Singapore, Singapore 117597, Singapore.
  • 6 Department of Physiology, National University of Singapore, Singapore 117597, Singapore; Life Sciences Institute, National University of Singapore, Singapore 117456, Singapore; Department of Cell and Molecular Biology, Karolinska Institute, Stockholm 17165, Sweden. Electronic address: phscfi@nus.edu.sg.
PMID: 30293939 DOI: 10.1016/j.chembiol.2018.09.007
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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-111163
    99.92%, p75NTR Agonist