AI Article Synopsis
- The SPIN1 protein, which reads methyl-lysine marks, is critical in various human diseases but has proven difficult to target due to a lack of effective inhibitors.
- Research led to the discovery of two new compounds: one that selectively inhibits SPIN1 and another that targets both SPIN1 and G9a/GLP, with the latter displaying high selectivity over other epigenetic targets.
- The study confirmed the binding of the dual inhibitor to a specific domain of SPIN1 and showed its effectiveness in disrupting SPIN1 interactions in cells, along with being bioavailable in mice, providing valuable tools for studying SPIN1's biological functions.
Article Abstract
The methyl-lysine reader protein SPIN1 plays important roles in various human diseases. However, targeting methyl-lysine reader proteins has been challenging. Very few cellularly active SPIN1 inhibitors have been developed. We previously reported that our G9a/GLP inhibitor UNC0638 weakly inhibited SPIN1. Here, we present our comprehensive structure-activity relationship study that led to the discovery of compound , a dual SPIN1 and G9a/GLP inhibitor, and compound (MS8535), a SPIN1 selective inhibitor. We solved the cocrystal structure of SPIN1 in complex with , confirming that occupied one of the three Tudor domains. Importantly, displayed high selectivity for SPIN1 over 38 epigenetic targets, including G9a/GLP, and concentration dependently disrupted the interactions of SPIN1 and H3 in cells. Furthermore, was bioavailable in mice. We also developed (MS8535N), which was inactive against SPIN1, as a negative control of . Collectively, these compounds are useful chemical tools to study biological functions of SPIN1.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11022035 | PMC |
| http://dx.doi.org/10.1021/acs.jmedchem.4c00121 | DOI Listing |
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