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Inhibition of Nuclear Receptor Binding SET Domain 2/Multiple Myeloma SET Domain by LEM-06 Implication for Epigenetic Cancer Therapies.

ABSTRACT: BACKGROUND:Multiple myeloma SET domain (MMSET)/nuclear receptor binding SET domain 2 (NSD2) is a lysine histone methyltransferase (HMTase) and bona fide oncoprotein found aberrantly expressed in several cancers, suggesting potential role for novel therapeutic strategies. In particular, MMSET/NSD2 is emerging as a target for therapeutic interventions against multiple myeloma, especially t(4;14) myeloma that is associated with a significantly worse prognosis than other biological subgroups. Multiple myeloma is the second most common hematological malignancy in the United States, after non-Hodgkin lymphoma and remains an incurable malignancy. Thus, effective therapeutic strategies are greatly needed. HMTases inhibitors are scarce and no NSDs inhibitors have been isolated. METHODS:We used homology modeling, molecular modeling simulations, virtual ligand screening, computational chemistry software for structure-activity relationship and performed in vitro H3K36 histone lysine methylation inhibitory assay using recombinant human NSD2-SET and human H3.1 histone. RESULTS:Here, we report the discovery of LEM-06, a hit small molecule inhibitor of NSD2, with an IC50 of 0.8 mM against H3K36 methylation in vitro. CONCLUSIONS:We propose LEM-06 as a hit inhibitor that is useful to further optimize for exploring the biology of NSD2. LEM-06 derivatives may pave the way to specific NSD2 inhibitors suitable for therapeutic efforts against malignancies.

SUBMITTER: di Luccio E

PROVIDER: S-EPMC4492355 | biostudies-literature | 2015 Jun

REPOSITORIES: biostudies-literature

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Inhibition of Nuclear Receptor Binding SET Domain 2/Multiple Myeloma SET Domain by LEM-06 Implication for Epigenetic Cancer Therapies.

di Luccio Eric E

Journal of cancer prevention 20150601 2

<h4>Background</h4>Multiple myeloma SET domain (MMSET)/nuclear receptor binding SET domain 2 (NSD2) is a lysine histone methyltransferase (HMTase) and bona fide oncoprotein found aberrantly expressed in several cancers, suggesting potential role for novel therapeutic strategies. In particular, MMSET/NSD2 is emerging as a target for therapeutic interventions against multiple myeloma, especially t(4;14) myeloma that is associated with a significantly worse prognosis than other biological subgroups ...[more]

PMID: 26151044

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Project description:In multiple myeloma, osteolytic lesions rarely heal because of persistent suppressed osteoblast differentiation resulting in a high fracture risk. Herein, chromatin immunoprecipitation analyses reveal that multiple myeloma cells induce repressive epigenetic histone changes at the Runx2 locus that prevent osteoblast differentiation. The most pronounced multiple myeloma-induced changes were at the Runx2-P1 promoter, converting it from a poised bivalent state to a repressed state. Previously, it was observed that multiple myeloma induces the transcription repressor GFI1 in osteoblast precursors, which correlates with decreased Runx2 expression, thus prompting detailed characterization of the multiple myeloma and TNFα-dependent GFI1 response element within the Runx2-P1 promoter. Further analyses reveal that multiple myeloma-induced GFI1 binding to Runx2 in osteoblast precursors and recruitment of the histone modifiers HDAC1, LSD1, and EZH2 is required to establish and maintain Runx2 repression in osteogenic conditions. These GFI1-mediated repressive chromatin changes persist even after removal of multiple myeloma. Ectopic GFI1 is sufficient to bind to Runx2, recruit HDAC1 and EZH2, increase H3K27me3 on the gene, and prevent osteogenic induction of endogenous Runx2 expression. Gfi1 knockdown in MC4 cells blocked multiple myeloma-induced recruitment of HDAC1 and EZH2 to Runx2, acquisition of repressive chromatin architecture, and suppression of osteoblast differentiation. Importantly, inhibition of EZH2 or HDAC1 activity in pre-osteoblasts after multiple myeloma exposure in vitro or in osteoblast precursors from patients with multiple myeloma reversed the repressive chromatin architecture at Runx2 and rescued osteoblast differentiation.Implications: This study suggests that therapeutically targeting EZH2 or HDAC1 activity may reverse the profound multiple myeloma-induced osteoblast suppression and allow repair of the lytic lesions. Mol Cancer Res; 15(4); 405-17. ©2017 AACR.

Dataset Information

Inhibition of Nuclear Receptor Binding SET Domain 2/Multiple Myeloma SET Domain by LEM-06 Implication for Epigenetic Cancer Therapies.

Publications

Inhibition of Nuclear Receptor Binding SET Domain 2/Multiple Myeloma SET Domain by LEM-06 Implication for Epigenetic Cancer Therapies.

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