Nuclear receptor binding SET domain proteins (NSDs) catalyze the mono- or dimethylation of histone 3 lysine 36 (H3K36me1 and H3K36me2), using -adenosyl-l-methionine (SAM) as a methyl donor. As a key member of the NSD family of proteins, NSD2 plays an important role in the pathogenesis and progression of various diseases such as cancers, inflammations, and infectious diseases, serving as a promising drug target. Developing potent and specific NSD2 inhibitors may provide potential novel therapeutics. Several NSD2 inhibitors and degraders have been discovered while remaining in the early stage of drug development. Excitingly, KTX-1001, a selective NSD2 inhibitor, has entered clinical trials. In this Perspective, the structures and functions of NSD2, its roles in various human diseases, and the recent advances in drug discovery strategies targeting NSD2 have been summarized. The challenges, opportunities, and future directions for developing NSD2 inhibitors and degraders are also discussed.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11092389 | PMC |
| http://dx.doi.org/10.1021/acs.jmedchem.3c00948 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Discovery of SET domain-binding primary alkylamine-tethered degraders for the simultaneous degradation of NSD2-long and RE-IIBP isoforms.
Eur J Med Chem
December 2024
Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan Tsuihang New District, Guangdong, 528400, China; Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; School of Pharmaceutical Sciences, Southern Medical University, Guangzhou Baiyun District, Guangzhou, Guangdong, 510515, China. Electronic address:
Nuclear receptor binding SET domain protein 2 (NSD2) is involved in various pathologic processes and is considered as an important target for cancer therapy. Due to alternative splicing, NSD2 has 3 isoforms: long, short and RE-IIBP. Although previous studies reported the degradation of PWWP1 domain-containing NSD2-long and short isoforms through PWWP1-binding molecules, the degradation of RE-IIBP which does not contain PWWP1 has been neglected to date.
View Article and Find Full Text PDFDownregulation of the splicing regulator NSRP1 confers resistance to CDK4/6 inhibitors via activation of interferon signaling in breast cancer.
J Biol Chem
December 2024
Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, Jiangsu, China; Jiangsu Key Laboratory of Experimental & Translational Non-Coding RNA Research, Yangzhou University, Yangzhou, Jiangsu, China. Electronic address:
The combination of CDK4/6 inhibitors (CDK4/6i) and endocrine therapy is the first-line therapy for ER+/Her2- breast cancer, however, the development of drug resistance limited the efficacy of the agents. Although activation of the IFN signaling pathway has been identified as a critical driver of intrinsic and acquired CDK4/6i resistance, it remains unknown how the IFN signaling pathway was activated in resistant cells. Here, we report that NSRP1, a regulator of alternative mRNA splicing is downregulated in CDK4/6i resistant breast cancer cells and contributes to CDK4/6i resistance by mediating alternative splicing of NSD2 mRNA and activation of the IFN signaling pathway.
View Article and Find Full Text PDFIdentification of potential methyltransferase NSD2 enzymatic inhibitors through a multi-step structure-based drug design.
Mol Divers
December 2024
Institute of Crystallography, Consiglio Nazionale Delle Ricerche (CNR), 70126, Bari, Italy.
Article Synopsis
Discovery of a Highly Potent and Selective Inhibitor Targeting Protein Lysine Methyltransferase NSD2.
J Med Chem
September 2024
Balance-Based Drug Discovery Laboratory, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, China.
The histone lysine methyltransferase NSD2 has been recognized as an attractive target for cancer treatment, due to the functional implication of its dysregulation in the initiation and progression of many cancers. Although considerable efforts have been made to develop NSD2 small-molecule inhibitors, highly potent and selective ones are still rarely available till now. Here, we report the discovery of a series of novel NSD2 inhibitors via an extensive SAR exploration of the privileged quinazoline scaffold within compound .
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!