AI Article Synopsis
- E2 enzymes, crucial in ubiquitin-like conjugation pathways, are challenging targets for drug development, with few noncovalent inhibitors identified so far.
- A small-molecule microarray (SMM) screening successfully identified an inhibitor for the Ubc9 enzyme, known for being "undruggable," leading to the chemical synthesis of the compound followed by various evaluations.
- The inhibitor showed binding to Ubc9 via nuclear magnetic resonance and was effective in inhibiting sumoylation at a concentration of 75 µM, demonstrating the SMM approach's potential for discovering E2 enzyme inhibitors.
Article Abstract
E2 enzymes in ubiquitin-like conjugation pathways are important, highly challenging pharmacological targets, and despite significant efforts, few noncovalent modulators have been discovered. Small-molecule microarray (SMM)-based screening was employed to identify an inhibitor of the "undruggable" small ubiquitin-like modifier (SUMO) E2 enzyme Ubc9. The inhibitor, a degradation product from a commercial screening collection, was chemically synthesized and evaluated in biochemical, mechanistic, and structure-activity relationship studies. Binding to Ubc9 was confirmed through the use of ligand-detected nuclear magnetic resonance, and inhibition of sumoylation in a reconstituted enzymatic cascade was found to occur with an IC of 75 µM. This work establishes the utility of the SMM approach for identifying inhibitors of E2 enzymes, targets with few known small-molecule modulators.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6344942 | PMC |
| http://dx.doi.org/10.1177/2472555216683937 | DOI Listing |
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