Target-Based Approach to Inhibitors of Histone Arginine Methyltransferases
Citations Over TimeTop 10% of 2007 papers
Abstract
Lysine and arginine methyltransferases participate in the post-translational modification of histones and regulate key cellular functions. So far only one arginine methyltransferase inhibitor discovered by random screening was available. We present the first target-based approach to protein arginine methyltransferase (PRMT) inhibitors. Homology models of human and Aspergillus nidulans PRMT1 were generated from available X-ray structures of rat PRMTs. The NCI diversity set was filtered by a target-based virtual screening to identify PRMT inhibitors. Employing a fungal PRMT for screening and a human enzyme for validation, we have identified seven inhibitors of PRMTs in vitro. Hit validation was achieved for two new inhibitors by antibody mediated detection of histone hypomethylation as well as Western blotting in cancer cells. Functional activity was proven by an observed block of estrogen receptor activation. Thus, valuable chemical tools and potential drug candidates could be identified.
Related Papers
- → The Protein Arginine Methyltransferases 1 and 5 affect Myc properties in glioblastoma stem cells(2019)41 cited
- → The Where and the How of PRMT5(2015)27 cited
- → Characterization of the Drosophila protein arginine methyltransferases DART1 and DART4(2004)70 cited
- Modulation of the tumor suppressor p53 pathway by arginine methyltransferases(2008)
- → The Protein Arginine Methyltransferases 1 and 5 affect Myc properties in glioblastoma stem cells.(2019)