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디 루시오, 에릭 대한암예방학회 2011 Journal of cancer prevention Vol.16 No.2
Both genetic and epigenetic alterations are responsible for the stepwise initiation and progression of cancers. Only epigenetic aberrations can be reversible, allowing the malignant cell population to revert to a more benign phenotype. The epigenetic therapy of cancers is emerging as an effective and valuable approach to both chemotherapy and the chemoprevention of cancer. The utilization of epigenetic targets that include histone methyltransferase (HMTase), histone deacetylase, and DNA methyltransferase, are emerging as key therapeutic targets. The nuclear receptor binding SET domain (NSD) protein is a family of three HMTases, NSD1, NSD2/MMSET/WHSC1, and NSD3/WHSC1L1, and plays a critical part in chromatin integrity as evidenced by a growing number of conditions linked to the alterations or amplification of NSD1, NSD2, or NSD3. NSD1, NSD2 and NSD3 are associated with multiple cancers. The amplification of either NSD1 or NSD2 triggers the cellular transformation and thus is key in the early carcinogenesis events. In most cases, reducing the levels of NSDs would suppress cancer growth. The NSD pathways, however, are not well understood. Recently, a partial crystal structure of the ligandless SET domain of NSD1 has been published enabling further studies toward a structure-based drug design effort on the NSD family. Here, we use computational methods to model the binding of the natural ligand histone H4K20 on the SET domain of NSD1. Our findings unravel a critical insight into an autoregulatory mechanism driven by the flexibility of the post-SET loop region and we prospect its special value for developing novel anticancer drugs. (Cancer Prev Res 16, 93-101, 2011)
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디 루시오, 에릭 대한암예방학회 2011 Journal of cancer prevention Vol.16 No.3
The transcriptional coactivator peroxisome proliferator-activated receptor coactivator-1α (PGC-1α/Ppargc1α) plays a central role in controlling and modulating the expression of mitochondrial genes. High levels of PGC-1α are linked to numerous pathological conditions and multiple pathways in relation with ROS detoxification, cancers, Alzheimer’s disease, stress response, circadian clock function, hepatic metabolism,strokes, cardiovascular diseases, Huntington’s disease and aging. PGC-1α has been cited as a potential new therapeutic target in the prevention of cancers and cardiovascular diseases by the mean of modulating the PGC-1α dependent-pathways using peptides targeting the Leu-Xaa-Xaa- Leu-Leu (LxxLL)domain of PGC-1α. LxxLL functional domain is key in many protein-protein interactions. New therapeutics are sorely needed to prevent and cure cancers along with the deterrence of cardiovascular diseases. In this study, using computational modeling tools, we provide structural insights into the design of small peptides to mimic the PGC-1α LxxLL domain to compete against PGC-1α in a bid to ultimately regulate the pathway. (Cancer Prev Res 16, 210-215, 2011)
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디 루시오, 에릭 대한암예방학회 2015 Journal of cancer prevention Vol.20 No.2
Background:Multiple myeloma SET domain (MMSET)/nuclear receptor binding SET domain 2 (NSD2) is a lysine histone methyltransferase (HMTase) and bona fideoncoprotein 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 secondmost 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 IC50of 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.
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