MAY 30, 2018 10:30 AM PDT
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Inhibitors of NSD2 Discovered by High-Throughput Screening with a Nucleosome Substrate
Presented at the Lab Automation 2018 Virtual Event
CONTINUING EDUCATION (CME/CE/CEU) CREDITS: P.A.C.E. CE
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Speakers:
  • Senior Research Scientist, Biology, Division of Pre-Clinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health
    Biography
      Dr. Nathan P. Coussens is a Senior Research Scientist in the Division of Pre-Clinical Innovation at the National Center for Advancing Translational Sciences (NCATS). He earned a Ph.D. in biochemistry from the University of Iowa, where he applied structural and biophysical approaches to the study of host-pathogen interactions. As a postdoctoral fellow of the Interdisciplinary Immunology Program at the University of Iowa, he utilized X-ray crystallography and thermodynamic binding studies to inform the development of small molecules that target a host evasion mechanism exploited by families of pathogenic bacteria. Prior to joining NCATS in 2013, Dr. Coussens was a postdoctoral fellow at the National Cancer Institute where he combined biophysical studies, cell biology, and high-resolution imaging to interrogate molecular signaling events initiated by the T cell antigen receptor. At NCATS, Dr. Coussens applies his diverse scientific background to develop and optimize novel biochemical and cell-based assays for high-throughput screening. He works with a highly collaborative and multidisciplinary team to develop small molecule probes relevant to a variety of human diseases. Dr. Coussens also serves as editor-in-chief of the Assay Guidance Manual, a growing online eBook of best practices for preclinical assay development and implementation that has become the go-to resource for scientists in industry and academia.

    Abstract:

    NSD2 catalyzes the mono- and di-methylation of the e-amine of lysine 36 from histone H3, utilizing the methyl donor S-adenosyl-L-methionine. Increased catalytic activity of NSD2, either by overexpression or point mutations, is associated with multiple human cancers. To date, potent, selective and cell-active NSD2 inhibitors have not been described. A platform was established for the discovery of selective NSD2 inhibitors from quantitative high-throughput screening in a 1536-well format using a nucleosome substrate. Active compounds from the primary screen were triaged by a panel of assays and tested against two clinically relevant NSD2 mutants, E1099K and T1150A. Five confirmed inhibitors were further evaluated by a radiolabeled validation assay, surface plasmon resonance studies, methyltransferase profiling, and histone methylation in U-2 OS cells. Several inhibitors bound the NSD2 catalytic SET domain and demonstrated activity in cells, which validates the use of this workflow for the discovery and development of selective NSD2 inhibitors.


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