Inhibition of Nuclear Receptor Binding SET Domain 2/Multiple Myeloma SET Domain by LEM-06 Implication for Epigenetic Cancer Therapies
Journal of Cancer Prevention
;
: 113-120, 2015.
Article
in English
| WPRIM
| ID: wpr-30137
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.
Full text:
Available
Index:
WPRIM (Western Pacific)
Main subject:
Prognosis
/
Structure-Activity Relationship
/
United States
/
Biology
/
Lymphoma, Non-Hodgkin
/
Histones
/
Drug Design
/
Models, Molecular
/
Chemistry
/
Mass Screening
Type of study:
Prognostic study
/
Screening study
Limits:
Humans
Country/Region as subject:
North America
Language:
English
Journal:
Journal of Cancer Prevention
Year:
2015
Type:
Article
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