St Andrews Research Repository

St Andrews University Home
View Item 
  •   St Andrews Research Repository
  • University of St Andrews Research
  • University of St Andrews Research
  • University of St Andrews Research
  • View Item
  •   St Andrews Research Repository
  • University of St Andrews Research
  • University of St Andrews Research
  • University of St Andrews Research
  • View Item
  •   St Andrews Research Repository
  • University of St Andrews Research
  • University of St Andrews Research
  • University of St Andrews Research
  • View Item
  • Login
JavaScript is disabled for your browser. Some features of this site may not work without it.

Targeting of the MYCN protein with small molecule c-MYC inhibitors

Thumbnail
View/Open
Westwood_2014_PLOSone_Targeting.pdf (2.055Mb)
Date
23/05/2014
Author
Muller, Inga
Larsson, Karin
Frenzel, Anna
Oliynyk, Ganna
Zirath, Hanna
Prochownik, Edward V.
Westwood, Nicholas J.
Henriksson, Marie Arsenian
Keywords
Circular-dichroism spectra
Secondary structure analyses
N-MYC
Neuronal differentiation
Neoplastic phenotype
MYC/MAX
Murine development
Induced apoptosis
Tumor dormancy
Neural-network
Q Science
Metadata
Show full item record
Altmetrics Handle Statistics
Altmetrics DOI Statistics
Abstract
Members of the MYC family are the most frequently deregulated oncogenes in human cancer and are often correlated with aggressive disease and/or poorly differentiated tumors. Since patients with MYCN-amplified neuroblastoma have a poor prognosis, targeting MYCN using small molecule inhibitors could represent a promising therapeutic approach. We have previously demonstrated that the small molecule 10058-F4, known to bind to the c-MYC bHLHZip dimerization domain and inhibiting the c-MYC/MAX interaction, also interferes with the MYCN/MAX dimerization in vitro and imparts anti-tumorigenic effects in neuroblastoma tumor models with MYCN overexpression. Our previous work also revealed that MYCN-inhibition leads to mitochondrial dysfunction resulting in accumulation of lipid droplets in neuroblastoma cells. To expand our understanding of how small molecules interfere with MYCN, we have now analyzed the direct binding of 10058-F4, as well as three of its analogs; #474, #764 and 10058-F4(7RH), one metabolite C-m/z 232, and a structurally unrelated c-MYC inhibitor 10074-G5, to the bHLHZip domain of MYCN. We also assessed their ability to induce apoptosis, neurite outgrowth and lipid accumulation in neuroblastoma cells. Interestingly, all c-MYC binding molecules tested also bind MYCN as assayed by surface plasmon resonance. Using a proximity ligation assay, we found reduced interaction between MYCN and MAX after treatment with all molecules except for the 10058-F4 metabolite C-m/z 232 and the non-binder 10058-F4(7RH). Importantly, 10074-G5 and 10058-F4 were the most efficient in inducing neuronal differentiation and lipid accumulation in MYCN-amplified neuroblastoma cells. Together our data demonstrate MYCN-binding properties for a selection of small molecules, and provide functional information that could be of importance for future development of targeted therapies against MYCN-amplified neuroblastoma.
Citation
Muller , I , Larsson , K , Frenzel , A , Oliynyk , G , Zirath , H , Prochownik , E V , Westwood , N J & Henriksson , M A 2014 , ' Targeting of the MYCN protein with small molecule c-MYC inhibitors ' , PLoS One , vol. 9 , no. 5 , e97285 . https://doi.org/10.1371/journal.pone.0097285
Publication
PLoS One
Status
Peer reviewed
DOI
https://doi.org/10.1371/journal.pone.0097285
ISSN
1932-6203
Type
Journal article
Rights
Copyright: © 2014 Müller et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. http://creativecommons.org/licenses/by/4.0/
Description
This study was funded by grants from the Swedish Research Council and the Swedish Cancer Society. IM and HZ were recipients of graduate student grants from KI (KID), MAH was recipient of a Senior Investigator Award from the Swedish Cancer Society, and NJW was a Royal Society University Research Fellow when this work began.
Collections
  • University of St Andrews Research
URL
http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0097285
URI
http://hdl.handle.net/10023/4978

Items in the St Andrews Research Repository are protected by copyright, with all rights reserved, unless otherwise indicated.

Advanced Search

Browse

All of RepositoryCommunities & CollectionsBy Issue DateNamesTitlesSubjectsClassificationTypeFunderThis CollectionBy Issue DateNamesTitlesSubjectsClassificationTypeFunder

My Account

Login

Open Access

To find out how you can benefit from open access to research, see our library web pages and Open Access blog. For open access help contact: openaccess@st-andrews.ac.uk.

Accessibility

Read our Accessibility statement.

How to submit research papers

The full text of research papers can be submitted to the repository via Pure, the University's research information system. For help see our guide: How to deposit in Pure.

Electronic thesis deposit

Help with deposit.

Repository help

For repository help contact: Digital-Repository@st-andrews.ac.uk.

Give Feedback

Cookie policy

This site may use cookies. Please see Terms and Conditions.

Usage statistics

COUNTER-compliant statistics on downloads from the repository are available from the IRUS-UK Service. Contact us for information.

© University of St Andrews Library

University of St Andrews is a charity registered in Scotland, No SC013532.

  • Facebook
  • Twitter