9exw
From Proteopedia
Crystal structure of the PWWP1 domain of NSD2 bound by compound 17.
Structural highlights
DiseaseNSD2_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. FunctionNSD2_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 PubMedDysregulation of histone methyl transferase nuclear receptor-binding SET domain 2 (NSD2) has been implicated in several hematological and solid malignancies. NSD2 is a large multidomain protein that carries histone writing and histone reading functions. To date, identifying inhibitors of the enzymatic activity of NSD2 has proven challenging in terms of potency and SET domain selectivity. Inhibition of the NSD2-PWWP1 domain using small molecules has been considered as an alternative approach to reduce NSD2-unregulated activity. In this article, we present novel computational chemistry approaches, encompassing free energy perturbation coupled to machine learning (FEP/ML) models as well as virtual screening (VS) activities, to identify high-affinity NSD2 PWWP1 binders. Through these activities, we have identified the most potent NSD2-PWWP1 binder reported so far in the literature: compound 34 (pIC(50) = 8.2). The compounds identified herein represent useful tools for studying the role of PWWP1 domains for inhibition of human NSD2. Identification of Novel Potent NSD2-PWWP1 Ligands Using Structure-Based Design and Computational Approaches.,Carlino L, Astles PC, Ackroyd B, Ahmed A, Chan C, Collie GW, Dale IL, O'Donovan DH, Fawcett C, di Fruscia P, Gohlke A, Guo X, Hao-Ru Hsu J, Kaplan B, Milbradt AG, Northall S, Petrovic D, Rivers EL, Underwood E, Webb A J Med Chem. 2024 May 15. doi: 10.1021/acs.jmedchem.4c00215. PMID:38748070[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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