ArticleThe Journal of biological chemistry2018
High-throughput screening with nucleosome substrate identifies small-molecule inhibitors of the human histone lysine methyltransferase NSD2.
Article in The Journal of biological chemistry, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 36 papers.
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Who cites it
36 citing papers in PubMed, 75 citations in OpenAlex.
- NSD Family-Mediated H3K36 Methylation in Human Cancer: Mechanisms and Therapeutic Opportunities.Biomedicines · 2025Review
- Chromatin Regulatory Targets for Anticancer Therapeutics.Chemical reviews · 2025Review
- Identification of potential methyltransferase NSD2 enzymatic inhibitors through a multi-step structure-based drug design.Molecular diversity · 2025Article
- Research status of small molecule inhibitors, probes, and degraders of NSDs: a comprehensive review.Future medicinal chemistry · 2025Review
- NSD proteins in anti-tumor immunity and their therapeutic targeting by protein degraders.Cellular and molecular life sciences : CMLS · 2025Review
- Discovery of a novel class NSD2 inhibitor for multiple myeloma with t(4;14)Blood neoplasia · 2025Article
- NSD family proteins: Rising stars as therapeutic targets.Cell insight · 2024Review
- Article
- Identification of a Protein Arginine Methyltransferase 7 (PRMT7)/Protein Arginine Methyltransferase 9 (PRMT9) Inhibitor.Journal of medicinal chemistry · 2023Article
- Recent advances in developing degraders & inhibitors of lysine methyltransferases.Current opinion in chemical biology · 2023Review
- Drug Discovery Targeting Nuclear Receptor Binding SET Domain Protein 2 (NSD2).Journal of medicinal chemistry · 2023Review
- Discovery of a Potent and Selective Targeted NSD2 Degrader for the Reduction of H3K36me2.Journal of the American Chemical Society · 2023Article
- NSD2 as a Promising Target in Hematological Disorders.International journal of molecular sciences · 2022Review
- Turning Nonselective Inhibitors of Type I Protein Arginine Methyltransferases into Potent and Selective Inhibitors of Protein Arginine Methyltransferase 4 through a Deconstruction-Reconstruction and Fragment-Growing Approach.Journal of medicinal chemistry · 2022Article
- Targeting Histone Epigenetic Modifications and DNA Damage Responses in Synthetic Lethality Strategies in Cancer?Cancers · 2022Article
- Discovery of a First-in-Class Degrader for Nuclear Receptor Binding SET Domain Protein 2 (NSD2) and Ikaros/Aiolos.Journal of medicinal chemistry · 2022Article
- The role of NSD1, NSD2, and NSD3 histone methyltransferases in solid tumors.Cellular and molecular life sciences : CMLS · 2022Review
- Exploring Methods of Targeting Histone Methyltransferases and Their Applications in Cancer Therapeutics.ACS chemical biology · 2022Review
- Lysine methyltransferase inhibitors: where we are now.RSC chemical biology · 2022Review
- Structural basis of the regulation of the normal and oncogenic methylation of nucleosomal histone H3 Lys36 by NSD2.Nature communications · 2021Article
Corrections and comments
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Authors and funding
20 authors at 3 institutions in 1 country.
Funding
Abstract
The histone lysine methyltransferase nuclear receptor-binding SET domain protein 2 (NSD2, also known as WHSC1/MMSET) is an epigenetic modifier and is thought to play a driving role in oncogenesis. Both NSD2 overexpression and point mutations that increase its catalytic activity are associated with several human cancers. Although NSD2 is an attractive therapeutic target, no potent, selective, and bioactive small molecule inhibitors of NSD2 have been reported to date, possibly due to the challenges of developing high-throughput assays for NSD2. Here, to establish a platform for the discovery and development of selective NSD2 inhibitors, we optimized and implemented multiple assays. We performed quantitative high-throughput screening with full-length WT NSD2 and a nucleosome substrate against a diverse collection of bioactive small molecules comprising 16,251 compounds. We further interrogated 174 inhibitory compounds identified in the primary screen with orthogonal and counter assays and with activity assays based on the clinically relevant NSD2 variants E1099K and T1150A. We selected five confirmed inhibitors for follow-up, which included a radiolabeled validation assay, surface plasmon resonance studies, methyltransferase profiling, and histone methylation in cells. We found that all five NSD2 inhibitors bind the catalytic SET domain and one exhibited apparent activity in cells, validating the workflow and providing a template for identifying selective NSD2 inhibitors. In summary, we have established a robust discovery pipeline for identifying potent NSD2 inhibitors from small-molecule libraries.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.