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Identification of LEM-14 inhibitor of the oncoprotein NSD2

Yunpeng Shen1, Masayo Morishita2, Doohyun Lee3

  • 1Department 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.

Biochemical and Biophysical Research Communications
|November 26, 2018
PubMed

Insights

Researchers developed LEM-14 and LEM-14-1189, novel inhibitors targeting NSD2 (MMSET), a key protein in multiple myeloma. These compounds offer new tools for studying NSD protein biology and developing targeted cancer therapies.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Oncology

Background:

  • The NSD family (NSD1, NSD2, NSD3) are histone lysine methyltransferases crucial for chromatin regulation.
  • NSD proteins are oncoproteins driving tumor development, making them important drug targets.
  • Selective NSD2 inhibition is a therapeutic strategy for multiple myeloma (MM), particularly the t(4;14) translocation subtype.

Purpose of the Study:

  • To discover and characterize novel inhibitors of NSD proteins.
  • To develop chemical tools for exploring NSD protein biology.
  • To advance the development of targeted therapies for hematological malignancies.

Main Methods:

  • In vitro biochemical assays to determine inhibitory activity (IC50 values) against NSD1, NSD2, and NSD3.
  • Chemical synthesis of novel NSD inhibitors and their derivatives.
  • Comparative analysis of inhibitor selectivity across the NSD family.

Main Results:

  • Discovery of LEM-14, a specific inhibitor of NSD2 with an in vitro IC50 of 132 μM, inactive against NSD1 and NSD3.
  • Characterization of LEM-14-1189, a derivative with differential inhibitory profiles: IC50 of 418 μM (NSD1), 111 μM (NSD2), and 60 μM (NSD3).
  • Demonstrated selectivity of LEM-14 for NSD2 and differential activity of LEM-14-1189 across NSD family members.

Conclusions:

  • LEM-14 and LEM-14-1189 serve as valuable chemical probes for studying NSD protein functions.
  • These compounds represent significant progress toward the development of potent and selective therapeutic inhibitors for NSD-driven cancers.
  • The findings support further investigation of NSD inhibitors for multiple myeloma and other malignancies.
Keywords:
Drug-designEpigenetic therapy of cancerHistone-lysine methyltransferaseInhibitorsMultiple myelomaNSD2

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