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Updated: Dec 10, 2025

Assays for Validating Histone Acetyltransferase Inhibitors
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Covalent inhibition of NSD1 histone methyltransferase

Huang Huang1, Christina A Howard1,2, Sergei Zari1

  • 1Department of Pathology, University of Michigan, Ann Arbor, MI, USA.

Nature Chemical Biology
|September 2, 2020
PubMed

Insights

Researchers developed novel irreversible small-molecule inhibitors targeting the NSD1 SET domain, a key protein in aggressive leukemia. These inhibitors show promise in blocking cancer cell growth and gene expression, offering new therapeutic avenues.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Oncology

Background:

  • The nuclear receptor-binding SET domain (NSD) family of histone methyltransferases is implicated in various cancers, notably aggressive acute leukemia driven by NUP98-NSD1 translocations.
  • NSD proteins are attractive drug targets, but their autoinhibited SET domain conformation poses challenges for inhibitor design.

Purpose of the Study:

  • To develop the first-in-class irreversible small-molecule inhibitors targeting the NSD1 SET domain.
  • To elucidate the structural basis for NSD1 inhibition.

Main Methods:

  • Fragment-based screening followed by chemical optimization.
  • X-ray crystallography to determine the structure of NSD1 in complex with a covalent inhibitor.
  • Assessment of on-target activity in NUP98-NSD1 leukemia cells.

Main Results:

  • Development of irreversible small-molecule inhibitors of the NSD1 SET domain.
  • Crystal structure revealing a conformational change and a targetable pocket.
  • Demonstration of BT5's on-target activity, including inhibition of H3K36 dimethylation, gene downregulation, and impaired colony formation in patient samples.

Conclusions:

  • The developed covalent inhibitors represent a breakthrough in targeting NSD histone methyltransferases.
  • Structural insights facilitate the design of next-generation potent and selective NSD inhibitors for leukemia treatment.

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