A Small Molecule Targeting the Transmembrane Domain of Death Receptor p75NTR Induces Melanoma Cell Death and Reduces Tumor Growth

Eddy T H Goh; Zhi Lin; Bo Young Ahn; Vanessa Lopes-Rodrigues; Ngoc Ha Dang; Shuhailah Salim; Bryan Berger; Brian Dymock; Donna L Senger; Carlos F Ibáñez

doi:10.1016/j.chembiol.2018.09.007

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.

Authors

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 p75^NTR that induced profound conformational changes and receptor activity. The compound triggered apoptotic cell death dependent on p75^NTR 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