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Peer-reviewedCC BY-NC-ND 4.0ACS Omega

Discovery of MYC/NSD3S Protein–Protein Interaction Negative Modulators with a Live Cell Nanoluciferase Protein-Fragment Complementation uHTS Assay

  • Sebastián Vera-Molina1,2
  • Diego Acosta-Yanez3
  • Ebonny Olivera1
  • Esteban Romero-Vera1
  • Carlos Farkas1,2
  • Matías I. Hepp1,2
  • Alexis Salas-Burgos2,3
  • Yuhong Du4
  • Valentina Gonzalez-Pecchi1,2
4 affiliations
  1. 1Universidad Catolica de la Santisima Concepcion , , ,
  2. 2Centro Territorial de Investigación Oncológica (CTIOi) , ,
  3. 3Universidad de Concepción , , ,
  4. 4Emory University School of Medicine , , , ,
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Abstract

Protein–protein interactions (PPIs) are central to physiological and pathophysiological processes. Identifying PPI modulators is the first step toward the development of new treatments. c-MYC (MYC), a key oncogene, interacts with NSD3S, stabilizing its structure and enhancing the oncogenic effect. In this work, we developed the NanoPCA assay in live cells in a 1536-well uHTS format to monitor the MYC/NSD3S PPI. We validated the platform by screening 12,000 compounds. The actions of several dose-dependent modulators were confirmed. Using orthogonal assays (immunoprecipitation, MYC reporter, and viability), we identified ethoxysanguinarine and withaferin A as potential negative modulators. Additionally, PPI in silico modeling and identification of key interaction points (hotspots) were performed to understand how the compounds may bind, revealing their potential ability to block the MYC/NSD3S PPI. These represent initial chemical tools that disrupt the MYC/NSD3S PPI signal in live cell assays and biochemical lysates, laying the foundation for targeted therapies against MYC/NSD3S-dependent cancers.

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Cite

BibTeXRIS
BibTeX
@article{veramolina2026discovery,
  title = {{Discovery of MYC/NSD3S Protein–Protein Interaction Negative Modulators with a Live Cell Nanoluciferase Protein-Fragment Complementation uHTS Assay}},
  author = {Sebastián Vera-Molina and Diego Acosta-Yanez and Ebonny Olivera and Esteban Romero-Vera and Carlos Farkas and Matías I. Hepp and Alexis Salas-Burgos and Yuhong Du and Valentina Gonzalez-Pecchi},
  journal = {ACS Omega},
  year = {2026},
  month = oct,
  doi = {10.1021/acsomega.6c03996},
  url = {https://pubs.acs.org/acsodf/article/11/41/62689/5445339/Discovery-of-MYC-NSD3S-Protein-Protein-Interaction},
  note = {CC BY-NC-ND 4.0},
}
RIS
TY  - JOUR
TI  - Discovery of MYC/NSD3S Protein–Protein Interaction Negative Modulators with a Live Cell Nanoluciferase Protein-Fragment Complementation uHTS Assay
AU  - Sebastián Vera-Molina
AU  - Diego Acosta-Yanez
AU  - Ebonny Olivera
AU  - Esteban Romero-Vera
AU  - Carlos Farkas
AU  - Matías I. Hepp
AU  - Alexis Salas-Burgos
AU  - Yuhong Du
AU  - Valentina Gonzalez-Pecchi
PY  - 2026
DA  - 2026/10/06
JO  - ACS Omega
DO  - 10.1021/acsomega.6c03996
UR  - https://pubs.acs.org/acsodf/article/11/41/62689/5445339/Discovery-of-MYC-NSD3S-Protein-Protein-Interaction
AB  - Protein–protein interactions (PPIs) are central to physiological and pathophysiological processes. Identifying PPI modulators is the first step toward the development of new treatments. c-MYC (MYC), a key oncogene, interacts with NSD3S, stabilizing its structure and enhancing the oncogenic effect. In this work, we developed the NanoPCA assay in live cells in a 1536-well uHTS format to monitor the MYC/NSD3S PPI. We validated the platform by screening 12,000 compounds. The actions of several dose-dependent modulators were confirmed. Using orthogonal assays (immunoprecipitation, MYC reporter, and viability), we identified ethoxysanguinarine and withaferin A as potential negative modulators. Additionally, PPI in silico modeling and identification of key interaction points (hotspots) were performed to understand how the compounds may bind, revealing their potential ability to block the MYC/NSD3S PPI. These represent initial chemical tools that disrupt the MYC/NSD3S PPI signal in live cell assays and biochemical lysates, laying the foundation for targeted therapies against MYC/NSD3S-dependent cancers.
SN  - 2470-1343
ER  -