期刊
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
卷 508, 期 1, 页码 102-108出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.bbrc.2018.11.037
关键词
Epigenetic therapy of cancer; Multiple myeloma; Histone-lysine methyltransferase; NSD2; Inhibitors; Drug-design
资金
- Basic Science Research Program of the National Research Foundation of Korea - Ministry of Education, Science and Technology of Korea [NRF-2018R1D1A1B07049298, NRF-2017R1A1A1A05001129, NRF-2016R1D1A1B01014286]
- Kyungpook National University
The NSD family (NSD1, NSD2/MMSET/WHSC1, and NSD3/WHSC1L1) are histone lysine methyl-transferases (HMTases) essential for chromatin regulation. The NSD5 are oncoproteins, drivers of a number of tumors and are considered important drug-targets but the lack of potent and selective inhibitors hampers further therapeutic development and limits exploration of their biology. In particular, MMSET/NSD2 selective inhibition is being pursued for therapeutic interventions against multiple myeloma (MM) cases, especially in multiple myeloma t(4;14)(p16.3;q32) translocation that is associated with a significantly worse prognosis than other MM subgroups. Multiple myeloma is the second most common hematological malignancy, after non-Hodgkin lymphoma and remains an incurable malignancy. Here we report the discovery of LEM-14, an NSD2 specific inhibitor with an in vitro IC50 of 132 mu M and that is inactive against the closely related NSD1 and NSD3. LEM-14-1189, a LEM-14 derivative, differentially inhibits the NSDs with in vitro IC50 of 418 mu M (NSD1), IC50 of 111 mu M (NSD2) and IC50 of 60 mu M (NSD3). We propose LEM-14 and derivative LEM-14-1189 as tools for studying the biology of the NSD5 and constitute meaningful steps toward potent NSDs therapeutic inhibitors. (C) 2018 Elsevier Inc. All rights reserved.
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