Identification of LEM-14 inhibitor of the oncoprotein NSD2

Yunpeng Shen; Masayo Morishita; Doohyun Lee; Shinae Kim; Taeho Lee; Damiaan E H F Mevius; Yeonjeong Roh; Eric di Luccio

doi:10.1016/j.bbrc.2018.11.037

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. Epub 2018 Nov 22.

Authors

Yunpeng Shen¹, Masayo Morishita², Doohyun Lee³, Shinae Kim³, Taeho Lee⁴, Damiaan E H F Mevius¹, Yeonjeong Roh⁵, Eric di Luccio⁶

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Catalytic Domain
Drug Design
Drug Discovery
Drug Evaluation, Preclinical
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
Histone-Lysine N-Methyltransferase / antagonists & inhibitors*
Histone-Lysine N-Methyltransferase / chemistry
Histone-Lysine N-Methyltransferase / genetics
Humans
Kinetics
Models, Molecular
Molecular Docking Simulation
Molecular Structure
Oncogene Proteins / antagonists & inhibitors*
Protein Conformation
Repressor Proteins / antagonists & inhibitors*
Repressor Proteins / chemistry
Repressor Proteins / genetics
User-Computer Interface

Substances

Enzyme Inhibitors
Oncogene Proteins
Repressor Proteins
Histone-Lysine N-Methyltransferase
NSD2 protein, human