6g2o
From Proteopedia
X-ray structure of NSD3-PWWP1 in complex with compound BI-9321
Structural highlights
DiseaseNSD3_HUMAN Note=Defects in WHSC1L1 may be involved in non small cell lung carcinomas (NSCLC). Amplified or overexpressed in NSCLC.[1] Note=A chromosomal aberration involving WHSC1L1 is found in childhood acute myeloid leukemia. Translocation t(8;11)(p11.2;p15) with NUP98. FunctionNSD3_HUMAN Histone methyltransferase. Preferentially methylates 'Lys-4' and 'Lys-27' of histone H3. H3 'Lys-4' methylation represents a specific tag for epigenetic transcriptional activation, while 'Lys-27' is a mark for transcriptional repression.[2] Publication Abstract from PubMedHere, 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. Fragment-based discovery of a chemical probe for the PWWP1 domain of NSD3.,Bottcher J, Dilworth D, Reiser U, Neumuller RA, Schleicher M, Petronczki M, Zeeb M, Mischerikow N, Allali-Hassani A, Szewczyk MM, Li F, Kennedy S, Vedadi M, Barsyte-Lovejoy D, Brown PJ, Huber KVM, Rogers CM, Wells CI, 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 XL, Fuchs JE, Mullauer B, Weiss-Puxbaum A, Gerstberger T, Boehmelt G, Vakoc CR, Arrowsmith CH, Pearson M, McConnell DB Nat Chem Biol. 2019 Aug;15(8):822-829. doi: 10.1038/s41589-019-0310-x. Epub 2019 , Jul 8. PMID:31285596[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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