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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

Dose-response curves of LEM-06 against nuclear receptor binding SET domain 2 (NSD2)-SET H3K36 mono-methylation activity. The dose-response curve and the IC50 calculation of LEM-06 were done using GraphPad Prism 6.0. Assays were done in triplicate individual experiments. The results were normalized against the control that does not contain any enzymes and only average data points are plotted.
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f3-jcp-20-113: Dose-response curves of LEM-06 against nuclear receptor binding SET domain 2 (NSD2)-SET H3K36 mono-methylation activity. The dose-response curve and the IC50 calculation of LEM-06 were done using GraphPad Prism 6.0. Assays were done in triplicate individual experiments. The results were normalized against the control that does not contain any enzymes and only average data points are plotted.

Mentions: The selected molecules were tested for inhibition of H3K36me1 by recombinant NSD2-SET with recombinant un-modified human histone H3.1 and compound LEM-06 inhibited NSD2-SET in vitro with an IC50 of 890 μM. LEM-06 in vitro IC50 value is slightly above other HMTase inhibitors such as MCTP39, TMDC 1c, AMI-1, AMI-5, AMI-6, AMI-9 and GSK343 IC50 range (Table 126,38,49–53, Fig. 3 and 4).


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)

Dose-response curves of LEM-06 against nuclear receptor binding SET domain 2 (NSD2)-SET H3K36 mono-methylation activity. The dose-response curve and the IC50 calculation of LEM-06 were done using GraphPad Prism 6.0. Assays were done in triplicate individual experiments. The results were normalized against the control that does not contain any enzymes and only average data points are plotted.
© Copyright Policy
Related In: Results  -  Collection

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

f3-jcp-20-113: Dose-response curves of LEM-06 against nuclear receptor binding SET domain 2 (NSD2)-SET H3K36 mono-methylation activity. The dose-response curve and the IC50 calculation of LEM-06 were done using GraphPad Prism 6.0. Assays were done in triplicate individual experiments. The results were normalized against the control that does not contain any enzymes and only average data points are plotted.
Mentions: The selected molecules were tested for inhibition of H3K36me1 by recombinant NSD2-SET with recombinant un-modified human histone H3.1 and compound LEM-06 inhibited NSD2-SET in vitro with an IC50 of 890 μM. LEM-06 in vitro IC50 value is slightly above other HMTase inhibitors such as MCTP39, TMDC 1c, AMI-1, AMI-5, AMI-6, AMI-9 and GSK343 IC50 range (Table 126,38,49–53, Fig. 3 and 4).

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