The First Potent, Selective and Cell-Active Allosteric Inhibitor of Protein Arginine Methyltransferase 3 (PRMT3)
Public Deposited- Last Modified
- February 26, 2019
- Creator
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Schmidt, Keith
- Affiliation: Eshelman School of Pharmacy
- Abstract
- PRMT3 is a type I arginine methyltransferase that catalyzes mono- and asymmetric dimethylation of arginine residues of various proteins. The protein has demonstrated through in vitro studies functionality in the maturation of ribosomes, a possible role in lipogenesis, and has several implications in various diseases. The purpose of this project was to develop and characterize a chemical probe that potently and selectively inhibits PRMT3 for further use in cellular and animal studies. SGC707, formerly known as UNC3108, is the first chemical probe of PRMT3 and was developed via structure based optimization. This potent allosteric inhibitor has been thoroughly characterized in a number of biochemical, biophysical, and cellular assays. The methods highlighted in this thesis describe synthesis of this chemical probe and characterization of this probe by an isothermal titration calorimetry assay. In addition to its high potency (IC50 = 31 ± 2 nM, KD = 53 ± 2 nM), SGC707 is selective for PRMT3 over >250 protein targets. It engages PRMT3 and potently inhibits its methyltransferase activity in cells. Initial pharmacokinetic studies also demonstrated that SGC707 is bioavailable and suitable for animal studies. Therefore, SGC707 is an excellent tool to further study the role of PRMT3 in health and disease.
- Date of publication
- spring 2015
- Keyword
- DOI
- Resource type
- Rights statement
- In Copyright
- Note
- Funding: None
- Advisor
- Jin, Jian
- Degree
- Doctor of Pharmacy
- Honors level
- Highest Honors
- Degree granting institution
- University of North Carolina at Chapel Hill
- Extent
- 15 pages
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