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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

Chemical structure of LEM-06. LEM-06 molecular weight is 492.7 Da; IC50 = 0.89 mM (NSD2-SET in vitro); Docking energy = −10.3 kcal/mol; wcLogP = 2.4, total polar surface area = 58.7 (Å2); number of rotated bonds = 4; number of violations of the Lipinski’s rule of five = 0; ZINC database ID: 20503683.
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f4-jcp-20-113: Chemical structure of LEM-06. LEM-06 molecular weight is 492.7 Da; IC50 = 0.89 mM (NSD2-SET in vitro); Docking energy = −10.3 kcal/mol; wcLogP = 2.4, total polar surface area = 58.7 (Å2); number of rotated bonds = 4; number of violations of the Lipinski’s rule of five = 0; ZINC database ID: 20503683.

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)

Chemical structure of LEM-06. LEM-06 molecular weight is 492.7 Da; IC50 = 0.89 mM (NSD2-SET in vitro); Docking energy = −10.3 kcal/mol; wcLogP = 2.4, total polar surface area = 58.7 (Å2); number of rotated bonds = 4; number of violations of the Lipinski’s rule of five = 0; ZINC database ID: 20503683.
© Copyright Policy
Related In: Results  -  Collection

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

f4-jcp-20-113: Chemical structure of LEM-06. LEM-06 molecular weight is 492.7 Da; IC50 = 0.89 mM (NSD2-SET in vitro); Docking energy = −10.3 kcal/mol; wcLogP = 2.4, total polar surface area = 58.7 (Å2); number of rotated bonds = 4; number of violations of the Lipinski’s rule of five = 0; ZINC database ID: 20503683.
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