ArticleNature chemical biology2020
Covalent inhibition of NSD1 histone methyltransferase.
Article in Nature chemical biology, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 43 papers, 1 of them a synthesis that pooled it.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
43 citing papers in PubMed, 1 synthesis or guideline pooled it, 87 citations in OpenAlex.
- NSD1 gene evolves under episodic selection within primates and mutations of specific exons in humans cause Sotos syndrome.BMC genomics · 2022Pooled it
- NSD Histone Methyltransferases in Solid Tumors: Biological Functions, Oncogenic Mechanisms and Therapeutic Targeting.International journal of molecular sciences · 2026Review
- 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
- Endogenous T cell responses to fusion-derived neoantigens in pediatric acute leukemias.Leukemia · 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
- SETD2 loss-of-function uniquely sensitizes cells to epigenetic targeting of NSD1-directed H3K36 methylation.Genome biology · 2025Article
- Case Report: SMARCA4-deficient NSCLC with brain metastasis harboring co-mutations in chromatin remodeling and DNA damage repair pathways.Frontiers in oncology · 2025Article
- Lysine and arginine methylation of transcription factors.Cellular and molecular life sciences : CMLS · 2024Review
- Epigenetic reprogramming in pediatric gliomas: from molecular mechanisms to therapeutic implications.Trends in cancer · 2024Review
- Epigenetic therapies targeting histone lysine methylation: complex mechanisms and clinical challenges.The Journal of clinical investigation · 2024Review
- Defining the Genomic Landscape of Diffuse Sclerosing Papillary Thyroid Carcinoma: Prognostic Implications of RET Fusions.Annals of surgical oncology · 2024Article
- Targeting fusion oncoproteins in childhood cancers: challenges and future opportunities for developing therapeutics.Journal of the National Cancer Institute · 2024Article
- NSD family proteins: Rising stars as therapeutic targets.Cell insight · 2024Review
- PIP4K2B Protein Regulation by NSD1 in HPV-Negative Head and Neck Squamous Cell Carcinoma.Cancers · 2024Article
- Therapeutic targeting in pediatric acute myeloid leukemia with aberrant HOX/MEIS1 expression.European journal of medical genetics · 2023Review
- 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
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Authors and funding
21 authors at 3 institutions in 1 country.
Funding
Abstract
The nuclear receptor-binding SET domain (NSD) family of histone methyltransferases is associated with various malignancies, including aggressive acute leukemia with NUP98-NSD1 translocation. While NSD proteins represent attractive drug targets, their catalytic SET domains exist in autoinhibited conformation, presenting notable challenges for inhibitor development. Here, we employed a fragment-based screening strategy followed by chemical optimization, which resulted in the development of the first-in-class irreversible small-molecule inhibitors of the nuclear receptor-binding SET domain protein 1 (NSD1) SET domain. The crystal structure of NSD1 in complex with covalently bound ligand reveals a conformational change in the autoinhibitory loop of the SET domain and formation of a channel-like pocket suitable for targeting with small molecules. Our covalent lead-compound BT5-demonstrates on-target activity in NUP98-NSD1 leukemia cells, including inhibition of histone H3 lysine 36 dimethylation and downregulation of target genes, and impaired colony formation in an NUP98-NSD1 patient sample. This study will facilitate the development of the next generation of potent and selective inhibitors of the NSD histone methyltransferases.
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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.