Data Analysis and Informatics

Combined experimental and computational HTS approaches to target NSD3-mediated protein-protein interactions for therapeutic discovery

Tuesday, February 6
11:00 AM - 11:30 AM
Location: 8

Lung cancer is the leading cancer killer in both men and women in the US, and the survival for lung cancer patients at five years remains as low as 15% or less. The recent advances in cancer genomics engaged with the expanded landscape of oncogenic protein-protein interaction network have enhanced our understanding of cancer biology offering new hope for novel therapeutic strategies to exploit lung cancer vulnerability. To address this urgent medical need, we utilized a highly robust high-throughput protein-protein interaction (PPI) screening platform and established a lung cancer-associated PPI network, termed OncoPPi. The OncoPPi links the cancer driver genes, both oncogenes and tumor suppressors and allows to identify new tumor dependencies to inform novel strategies for therapeutic interventions. As one example, the OncoPPi has revealed a direct interaction between MYC oncogene and NSD3 protein, which plays a critical role in regulation of chromatin remodeling through a direct association with BRD4. BRD4-MYC PPI suggests a novel BRD4 regulatory mechanism and a potential target for perturbing the NSD3-mediated oncogenic pathway. Thus, inhibition of interactions of NSD3 with MYC and BRD4 by small molecules would provide new tools to investigate the NSD3-dependent tumorigenesis, and will facilitate lung cancer drug development. To achieve this goal, we have developed a time-resolved fluorescence resonance energy transfer (TR-FRET) assay to monitor the interaction of NSD3S and MYC in miniaturized 1536-well ultra-high-throughput screening (uHTS) format. Furthermore, to identify compound scaffolds required for the efficient disruption of NSD3 PPIs, we have developed and applied an integrated computational workflow that combines classical cheminformatics approaches with the large-scale cross-validation virtual screening methods. Based on the promising data from our pilot screening, we have launched a large-scale screening campaign to discover potent and selective inhibitors of NSD3 interactions. Together, the OncoPPi network serves as a powerful resource to uncover new cancer vulnerabilities on oncogenic protein-protein interactions. Our complementary experimental and computational high-throughput approaches provide a robust workflow to discover novel inhibitors of challenging PPIs to facilitate anti-cancer drug development.

Andrey Ivanov

Instructor
Emory University

Computational and medicinal chemistry, biochemistry, cancer biology

Presentation(s):

Send Email for Andrey Ivanov


Assets

Combined experimental and computational HTS approaches to target NSD3-mediated protein-protein interactions for therapeutic discovery



Attendees who have favorited this

Please enter your access key

The asset you are trying to access is locked. Please enter your access key to unlock.

Send Email for Combined experimental and computational HTS approaches to target NSD3-mediated protein-protein interactions for therapeutic discovery