Author(s)
Hong Zeng
Published 3 Projects
Biochemistry Infectious Diseases Rheumatology Interstitial Lung Disease Macrophage Activation Syndrome
Matthieu Schapira
Associate Professor, University of Toronto
Published 8 Projects
Bioinformatics Biochemistry Pharmacology And Toxicology Cell Biology
Content
Video Abstract (AI generated) (01:30) Paper PreprintPRMT6 catalyzes monomethylation and asymmetric dimethylation of arginine residues in various proteins, plays important roles in biological processes and is associated with multiple cancers. While there are several reported PRMT6 inhibitors, a highly selective PRMT6 inhibitor has not been reported to date. Furthermore, allosteric inhibitors of protein methyltransferases are rare. Here we report the discovery and characterization of a first-in-class, highly selective allosteric inhibitor of PRMT6, SGC6870. SGC6870 is a potent PRMT6 inhibitor (IC50 = 77 {+/-} 6 nM) with outstanding selectivity for PRMT6 over a broad panel of other methyltransferases and non-epigenetic targets. Notably, the crystal structure of the PRMT6-SGC6870 complex and kinetic studies revealed SGC6870 binds a unique, induced allosteric pocket. Additionally, SGC6870 engages PRMT6 and potently inhibits its methyltransferase activity in cells. Moreover, SGC6870's enantiomer, SGC6870N, is inactive against PRMT6 and can be utilized as a negative control. Collectively, SGC6870 is a well-characterized PRMT6 chemical probe and valuable tool for further investigating PRMT6 functions in health and disease.
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Fengling Li. (2021, Sep 30).A First-in-class, Highly Selective and Cell-active AllostericInhibitor of Protein Arginine Methyltransferase 6 (PRMT6)[Video]. Scitok. https://scitok.com/project/p/a38f5345
Shen Yudao. "A First-in-class, Highly Selective and Cell-active AllostericInhibitor of Protein Arginine Methyltransferase 6 (PRMT6)" Scitok, uploaded by Li Fengling, 30 Sep, 2021, https://scitok.com/project/pa38f5345
Fengling Li. "A First-in-class, Highly Selective and Cell-active AllostericInhibitor of Protein Arginine Methyltransferase 6 (PRMT6)" Scitok. (Sep 30, 2021). https://scitok.com/project/p/a38f5345
Fengling Li (Sep 30, 2021). A First-in-class, Highly Selective and Cell-active AllostericInhibitor of Protein Arginine Methyltransferase 6 (PRMT6) Scitok. https://scitok.com/project/p/a38f5345
Fengling Li. A First-in-class, Highly Selective and Cell-active AllostericInhibitor of Protein Arginine Methyltransferase 6 (PRMT6)[video]. 2021 Sep 30. https://scitok.com/project/p/a38f5345
@online{al2006link, title={ A First-in-class, Highly Selective and Cell-active AllostericInhibitor of Protein Arginine Methyltransferase 6 (PRMT6) }, author={ Li, Fengling }, organization={Scitok}, month={ Sep }, day={ 30 }, year={ 2021 }, url = {https://scitok.com/project/p/a38f5345}, }