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Discovery of a potent and selective proteolysis targeting chimera (PROTAC) degrader of NSD3 histone methyltransferase.
- Source :
-
European Journal of Medicinal Chemistry . Sep2022, Vol. 239, pN.PAG-N.PAG. 1p. - Publication Year :
- 2022
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Abstract
- Nuclear receptor binding SET domain protein 3 (NSD3) is an attractive potential target in the therapy for human cancers. Herein, we report the discovery of a series of small-molecule NSD3 degraders based on the proteolysis targeting chimera (PROTAC) strategy. The represented compound 8 induces NSD3 degradation with DC 50 values of 1.43 and 0.94 μM in NCI–H1703 and A549 lung cancer cells, respectively, and shows selectivity over two other NSD proteins. 8 reduces histone H3 lysine 36 methylation and induces apoptosis and cell cycle arrest in lung cancer cells. Moreover, the RNA sequencing and immunohistochemistry assays showed that 8 downregulates NSD3-associated gene expression. Significantly, 8 , but not 1 (a reported NSD3-PWWP antagonist) could inhibit the cell growth of NCI–H1703 and A549 cells. A single administration of 8 effectively decreases the NSD3 protein level in lung cancer xenograft models. Therefore, this study demonstrated that inducing NSD3 degradation is a more effective approach inhibiting the function of NSD3 than blocking the NSD3-PWWP domain, which may provide a potential therapeutic approach for lung cancer. [Display omitted] • A potent and selective PROTAC degrader of NSD3 was designed, synthesized and evaluated. • Compound 8 decreased NSD3-associated genes and H3K36me3. • Compound 8 induced lung cancer cell growth arrest and apoptosis. • Compound 8 inhibited proliferation and clone formation in lung cancer cells. • A single dose of compound 8 effectively reduced NSD3 in xenograft tumor tissue in mice. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 02235234
- Volume :
- 239
- Database :
- Academic Search Index
- Journal :
- European Journal of Medicinal Chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 157819852
- Full Text :
- https://doi.org/10.1016/j.ejmech.2022.114528