2. Academic Validation
  3. Identification of LEM-14 inhibitor of the oncoprotein NSD2

Identification of LEM-14 inhibitor of the oncoprotein NSD2

  • Biochem Biophys Res Commun. 2019 Jan 1;508(1):102-108. doi: 10.1016/j.bbrc.2018.11.037.
Yunpeng Shen 1,  Masayo Morishita 2,  Doohyun Lee 3,  Shinae Kim 3,  Taeho Lee 4,  Damiaan E H F Mevius 1,  Yeonjeong Roh 5,  Eric di Luccio 6
Affiliations

Affiliations

  • 1 Department of Genetic Engineering, School of Life Sciences, College of Natural Sciences, Kyungpook National University, Daegu, 41566, Republic of Korea; Department of Food Biomaterials, College of Agriculture and Life Sciences, Kyungpook National University, Daegu, 41566, Republic of Korea.
  • 2 Department of Genetic Engineering, School of Life Sciences, College of Natural Sciences, Kyungpook National University, Daegu, 41566, Republic of Korea; 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; New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu, 41061, Republic of Korea.
  • 4 College of Pharmacy, Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu, 41566, Republic of Korea.
  • 5 Department of Genetic Engineering, School of Life Sciences, College of Natural Sciences, Kyungpook National University, Daegu, 41566, Republic of Korea.
  • 6 Department of Genetic Engineering, School of Life Sciences, College of Natural Sciences, Kyungpook National University, Daegu, 41566, Republic of Korea. Electronic address: diluccio@knu.ac.kr.
PMID: 30471851 DOI: 10.1016/j.bbrc.2018.11.037
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.

Keywords

Drug-design; Epigenetic therapy of cancer; Histone-lysine methyltransferase; Inhibitors; Multiple myeloma; NSD2.

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