Identification of LEM-14 inhibitor of the oncoprotein NSD2 |
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Authors: | Yunpeng Shen Masayo Morishita Doohyun Lee Shinae Kim Taeho Lee Damiaan EHF Mevius Yeonjeong Roh Eric di Luccio |
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Institution: | 1. Department of Genetic Engineering, School of Life Sciences, College of Natural Sciences, Kyungpook National University, Daegu, 41566, Republic of Korea;2. Institute of Agricultural Science and Technology, Kyungpook National University, Daegu, 41566, Republic of Korea;3. College of Pharmacy, Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu, 41566, Republic of Korea;4. New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu, 41061, Republic of Korea;5. Department of Food Biomaterials, College of Agriculture and Life Sciences, Kyungpook National University, Daegu, 41566, Republic of Korea |
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Abstract: | The NSD family (NSD1, NSD2/MMSET/WHSC1, and NSD3/WHSC1L1) are histone lysine methyltransferases (HMTases) essential for chromatin regulation. The NSDs 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?μM 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?μM (NSD1), IC50 of 111?μM (NSD2) and IC50 of 60?μM (NSD3). We propose LEM-14 and derivative LEM-14-1189 as tools for studying the biology of the NSDs and constitute meaningful steps toward potent NSDs therapeutic inhibitors. |
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Keywords: | Epigenetic therapy of cancer Multiple myeloma Histone-lysine methyltransferase NSD2 Inhibitors Drug-design NSD nuclear receptor binding SET domain MMSET Multiple Myeloma SET domain HMTase Histone lysine Methyltransferase AdoMET S-adenosylmethionine |
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