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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 E - J Cancer Prev (2015)

Bottom Line: Thus, effective therapeutic strategies are greatly needed.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.LEM-06 derivatives may pave the way to specific NSD2 inhibitors suitable for therapeutic efforts against malignancies.

View Article: PubMed Central - PubMed

Affiliation: School of Applied Biosciences, Kyungpook National University, Daegu, Korea.

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.

No MeSH data available.


Related in: MedlinePlus

Molecular details of the binding of LEM-06 into the histone-tail binding groove of nuclear receptor binding SET domain 2 Dashed yellow lines indicate hydrogen bonds.
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f5-jcp-20-113: Molecular details of the binding of LEM-06 into the histone-tail binding groove of nuclear receptor binding SET domain 2 Dashed yellow lines indicate hydrogen bonds.

Mentions: The weaker inhibition by LEM-06 could perhaps be explained by a weak stabilization in the SET domain with three hydrogen bonds for LEM-06 (Fig. 5). One possible explanation for a reduced inhibition by LEM-06 may lie in the molar refractivity of the tested molecules to effectively compete for the binding with histone H3.1.


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

di Luccio E - J Cancer Prev (2015)

Molecular details of the binding of LEM-06 into the histone-tail binding groove of nuclear receptor binding SET domain 2 Dashed yellow lines indicate hydrogen bonds.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4492355&req=5

f5-jcp-20-113: Molecular details of the binding of LEM-06 into the histone-tail binding groove of nuclear receptor binding SET domain 2 Dashed yellow lines indicate hydrogen bonds.
Mentions: The weaker inhibition by LEM-06 could perhaps be explained by a weak stabilization in the SET domain with three hydrogen bonds for LEM-06 (Fig. 5). One possible explanation for a reduced inhibition by LEM-06 may lie in the molar refractivity of the tested molecules to effectively compete for the binding with histone H3.1.

Bottom Line: Thus, effective therapeutic strategies are greatly needed.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.LEM-06 derivatives may pave the way to specific NSD2 inhibitors suitable for therapeutic efforts against malignancies.

View Article: PubMed Central - PubMed

Affiliation: School of Applied Biosciences, Kyungpook National University, Daegu, Korea.

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.

No MeSH data available.


Related in: MedlinePlus