Fragment-based discovery of a chemical probe for the PWWP1 domain of NSD3

Bottcher, J., Dilworth, D., Reiser, U., Neumuller, R. A., Schleicher, M., Petronczki, M., Zeeb, M., Mischerikow, N., Allali-Hassani, A., Szewczyk, M. M., Li, F., Kennedy, S., Vedadi, M., Barsyte-Lovejoy, D., Brown, P. J., Huber, K. V. M., Rogers, C. M., Wells, C. I., Fedorov, O., Rumpel, K., Zoephel, A., Mayer, M., Wunberg, T., Bose, D., Zahn, S., Arnhof, H., Berger, H., Reiser, C., Hormann, A., Krammer, T., Corcokovic, M., Sharps, B., Winkler, S., Haring, D., Cockcroft, X. L., Fuchs, J. E., Mullauer, B., Weiss-Puxbaum, A., Gerstberger, T., Boehmelt, G., Vakoc, C. R., Arrowsmith, C. H., Pearson, M., McConnell, D. B. (July 2019) Fragment-based discovery of a chemical probe for the PWWP1 domain of NSD3. Nat Chem Biol, 15 (8). pp. 822-829. ISSN 1552-4450

Abstract

Here, we report the fragment-based discovery of BI-9321, a potent, selective and cellular active antagonist of the NSD3-PWWP1 domain. The human NSD3 protein is encoded by the WHSC1L1 gene located in the 8p11-p12 amplicon, frequently amplified in breast and squamous lung cancer. Recently, it was demonstrated that the PWWP1 domain of NSD3 is required for the viability of acute myeloid leukemia cells. To further elucidate the relevance of NSD3 in cancer biology, we developed a chemical probe, BI-9321, targeting the methyl-lysine binding site of the PWWP1 domain with sub-micromolar in vitro activity and cellular target engagement at 1 microM. As a single agent, BI-9321 downregulates Myc messenger RNA expression and reduces proliferation in MOLM-13 cells. This first-in-class chemical probe BI-9321, together with the negative control BI-9466, will greatly facilitate the elucidation of the underexplored biological function of PWWP domains.

Item Type:	Paper
Subjects:	bioinformatics Investigative techniques and equipment > CRISPR diseases & disorders > cancer diseases & disorders bioinformatics > genomics and proteomics Investigative techniques and equipment organs, tissues, organelles, cell types and functions > cell types and functions > cell functions organs, tissues, organelles, cell types and functions > cell types and functions > cell types > cell line organs, tissues, organelles, cell types and functions > cell types and functions > cell types > cell line organs, tissues, organelles, cell types and functions > cell types and functions > cell types > cell line organs, tissues, organelles, cell types and functions > cell types and functions > cell functions > cell proliferation organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions Investigative techniques and equipment > CRISPR-Cas9 diseases & disorders > cancer > cancer types > leukemia organs, tissues, organelles, cell types and functions bioinformatics > genomics and proteomics > small molecules diseases & disorders > cancer > cancer types
CSHL Authors:	Vakoc, Christopher R.
Communities:	CSHL labs > Vakoc lab CSHL Cancer Center Program > Cancer Genetics and Genomics Program
Depositing User:	Matthew Dunn
Date:	8 July 2019
Date Deposited:	08 Aug 2019 13:43
Last Modified:	01 Feb 2024 20:43
Related URLs:	Publisher
URI:	https://repository.cshl.edu/id/eprint/38139

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