7vln | pdb_00007vln
NSD2-PWWP1 domain bound with an imidazol-5-yl benzonitrile compound
Structural highlights
Disease[NSD2_HUMAN] Wolf-Hirschhorn syndrome. A chromosomal aberration involving WHSC1 is a cause of multiple myeloma tumors. Translocation t(4;14)(p16.3;q32.3) with IgH. WHSC1 is located in the Wolf-Hirschhorn syndrome (WHS) critical region. WHS results from by sub-telomeric deletions in the short arm of chromosome 4. WHSC1 is deleted in every case, however deletion of linked genes contributes to both the severity of the core characteristics and the presence of the additional syndromic problems. Function[NSD2_HUMAN] Histone methyltransferase with histone H3 'Lys-27' (H3K27me) methyltransferase activity. Isoform 2 may act as a transcription regulator that binds DNA and suppresses IL5 transcription through HDAC recruitment.[1] [2] [3] Publication Abstract from PubMedOverexpression, point mutations, or translocations of protein lysine methyltransferase NSD2 occur in many types of cancer cells. Therefore, it was recognized as onco-protein and considered as a promising anticancer drug target. NSD2 consists of multiple domains including a SET catalytic domain and two PWWP domains binding to methylated histone proteins. Here, we reported our efforts to develop a series of NSD2-PWWP1 inhibitors, and further structure-based optimization resulted in a potent inhibitor 38, which has high selectivity toward the NSD2-PWWP1 domain. The detailed biological evaluation revealed that compound 38 can bind to NSD2-PWWP1 and then affect the expression of genes regulated by NSD2. The current discovery will provide a useful chemical probe to the future research in understanding the specific regulation mode of NSD2 by PWWP1 recognition and pave the way to develop potential drugs targeting NSD2 protein. Structure-Based Discovery of a Series of NSD2-PWWP1 Inhibitors.,Li N, Yang H, Liu K, Zhou L, Huang Y, Cao D, Li Y, Sun Y, Yu A, Du Z, Yu F, Zhang Y, Wang B, Geng M, Li J, Xiong B, Xu S, Huang X, Liu T J Med Chem. 2022 Jun 15. doi: 10.1021/acs.jmedchem.2c00709. PMID:35704853[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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