PMID- 30471851
OWN - NLM
STAT- MEDLINE
DCOM- 20190603
LR  - 20190816
IS  - 1090-2104 (Electronic)
IS  - 0006-291X (Linking)
VI  - 508
IP  - 1
DP  - 2019 Jan 1
TI  - Identification of LEM-14 inhibitor of the oncoprotein NSD2.
PG  - 102-108
LID - S0006-291X(18)32443-4 [pii]
LID - 10.1016/j.bbrc.2018.11.037 [doi]
AB  - 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 IC(50) of 132 muM 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 IC(50) of 418 muM (NSD1), IC(50) of 111 muM (NSD2) and 
      IC(50) of 60 muM (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.
CI  - Copyright (c) 2018 Elsevier Inc. All rights reserved.
FAU - Shen, Yunpeng
AU  - Shen Y
AD  - 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.
FAU - Morishita, Masayo
AU  - Morishita M
AD  - 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.
FAU - Lee, Doohyun
AU  - Lee D
AD  - 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.
FAU - Kim, Shinae
AU  - Kim S
AD  - 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.
FAU - Lee, Taeho
AU  - Lee T
AD  - College of Pharmacy, Research Institute of Pharmaceutical Sciences, Kyungpook 
      National University, Daegu, 41566, Republic of Korea.
FAU - Mevius, Damiaan E H F
AU  - Mevius DEHF
AD  - 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.
FAU - Roh, Yeonjeong
AU  - Roh Y
AD  - Department of Genetic Engineering, School of Life Sciences, College of Natural 
      Sciences, Kyungpook National University, Daegu, 41566, Republic of Korea.
FAU - di Luccio, Eric
AU  - di Luccio E
AD  - 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.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20181122
PL  - United States
TA  - Biochem Biophys Res Commun
JT  - Biochemical and biophysical research communications
JID - 0372516
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Oncogene Proteins)
RN  - 0 (Repressor Proteins)
RN  - EC 2.1.1.43 (Histone-Lysine N-Methyltransferase)
RN  - EC 2.1.1.43 (NSD2 protein, human)
SB  - IM
MH  - Catalytic Domain
MH  - Drug Design
MH  - Drug Discovery
MH  - Drug Evaluation, Preclinical
MH  - Enzyme Inhibitors/chemistry/*pharmacology
MH  - Histone-Lysine N-Methyltransferase/*antagonists & inhibitors/chemistry/genetics
MH  - Humans
MH  - Kinetics
MH  - Models, Molecular
MH  - Molecular Docking Simulation
MH  - Molecular Structure
MH  - Oncogene Proteins/*antagonists & inhibitors
MH  - Protein Conformation
MH  - Repressor Proteins/*antagonists & inhibitors/chemistry/genetics
MH  - User-Computer Interface
OTO - NOTNLM
OT  - Drug-design
OT  - Epigenetic therapy of cancer
OT  - Histone-lysine methyltransferase
OT  - Inhibitors
OT  - Multiple myeloma
OT  - NSD2
EDAT- 2018/11/26 06:00
MHDA- 2019/06/04 06:00
CRDT- 2018/11/26 06:00
PHST- 2018/10/29 00:00 [received]
PHST- 2018/11/06 00:00 [accepted]
PHST- 2018/11/26 06:00 [pubmed]
PHST- 2019/06/04 06:00 [medline]
PHST- 2018/11/26 06:00 [entrez]
AID - S0006-291X(18)32443-4 [pii]
AID - 10.1016/j.bbrc.2018.11.037 [doi]
PST - ppublish
SO  - Biochem Biophys Res Commun. 2019 Jan 1;508(1):102-108. doi: 
      10.1016/j.bbrc.2018.11.037. Epub 2018 Nov 22.