J Cancer Prev.  2015 Jun;20(2):113-120. 10.15430/JCP.2015.20.2.113.

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

• di Luccio

• KMID: 2171336
• DOI: http://doi.org/10.15430/JCP.2015.20.2.113

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.

Keyword

Epigenomics; Drug design; Histone-Lysine N-Methyltransferase; NSD2 protein; Antagonists & inhibitors

MeSH Terms

Biology
Chemistry
Drug Design
Epigenomics*
Hematologic Neoplasms
Histone-Lysine N-Methyltransferase
Histones
Humans
Inhibitory Concentration 50
Lymphoma, Non-Hodgkin
Lysine
Mass Screening
Methylation
Models, Molecular
Multiple Myeloma
Prognosis
Structure-Activity Relationship
United States
Histone-Lysine N-Methyltransferase
Histones
Lysine