Discovery of Small-Molecule Antagonists of the PWWP Domain of NSD2

Ferreira de Freitas, R.; Liu, Y.; Szewczyk, M.; Mehta, N.; Li, F.; McLeod, D.; Zepeda-Velazquez, C.; Dilworth, D.; Hanley, R. P.; Gibson, E.; Brown, P. J.; Al-Awar, R.; Ingerman James, L.; Arrowsmith, C. H.; Barsyte-Lovejoy, D.; Min, J.; Vedadi, M.; Schapira, M.; Allali-Hassani, A.

doi:10.1101/2020.11.25.398586

bioRxiv · 10.1101/2020.11.25.398586

Discovery of Small-Molecule Antagonists of the PWWP Domain of NSD2

Ferreira de Freitas, R.·Liu, Y.·Szewczyk, M.·Mehta, N.·Li, F.·McLeod, D.·Zepeda-Velazquez, C.·Dilworth, D.·Hanley, R. P.·Gibson, E.·Brown, P. J.·Al-Awar, R.·Ingerman James, L.·Arrowsmith, C. H.·Barsyte-Lovejoy, D.·Min, J.·Vedadi, M.·Schapira, M.·Allali-Hassani, A.

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Abstract

Increased activity of the lysine methyltrans-ferase NSD2 driven by translocation and activating mutations is associated with multiple myeloma and acute lymphoblastic leukemia, but no NSD2-targeting chemical probe has been reported to date. Here, we present the first antagonists that block the protein-protein interaction between the N-terminal PWWP domain of NSD2 and H3K36me2. Using virtual screening and experimental validation, we identified the small-molecule antagonist 3f, which binds to the NSD2-PWWP1 domain with a Kd of 3.4 M and abrogates histone H3K36me2 binding in cells. This study establishes an alternative approach to targeting NSD2 and provides a small-molecule antagonist that can be further optimized into a chemical probe to better understand the cellular function of this protein.

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Ferreira de Freitas, R., Liu, Y., Szewczyk, M., Mehta, N., Li, F., McLeod, D., Zepeda-Velazquez, C., Dilworth, D., Hanley, R. P., Gibson, E., Brown, P. J., Al-Awar, R., Ingerman James, L., Arrowsmith, C. H., Barsyte-Lovejoy, D., Min, J., Vedadi, M., Schapira, M., Allali-Hassani, A.. 2020-11-27. Discovery of Small-Molecule Antagonists of the PWWP Domain of NSD2. https://doi.org/10.1101/2020.11.25.398586

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