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Structure-Guided Discovery of Selective Antagonists for the Chromodomain of Polycomb Repressive Protein CBX7
Chunyan Ren1, Steven G Smith1, Kyoko Yap1
1Department of Structural and Chemical Biology and Department of Pediatrics, Icahn School of Medicine at Mount Sinai , New York, New York 10029, United States.
Abstract:
The chromobox 7 (CBX7) protein of the polycomb repressive complex 1 (PRC1) functions to repress transcription of tumor suppressor p16 (INK4a) through long noncoding RNA, ANRIL (antisense noncoding RNA in the INK4 locus) directed chromodomain (ChD) binding to trimethylated lysine 27 of histone H3 (H3K27me3), resulting in chromatin compaction at the INK4a/ARF locus. In this study, we report structure-guided discovery of two distinct classes of small-molecule antagonists for the CBX7ChD. Our Class A compounds, a series including analogues of the previously reported MS452, inhibit CBX7ChD/methyl-lysine binding by occupying the H3K27me3 peptide binding site, whereas our Class B compound, the newly discovered MS351, appears to inhibit H3K27me3 binding when CBX7ChD is bound to RNA. Our crystal structure of the CBX7ChD/MS351 complex reveals the molecular details of ligand recognition by the aromatic cage residues that typically engage in methyl-lysine binding. We further demonstrate that MS351 effectively induces transcriptional derepression of CBX7 target genes, including p16 (INK4a) in mouse embryonic stem cells and human prostate cancer PC3 cells. Thus, MS351 represents a new class of ChD antagonists that selectively targets the biologically active form of CBX7 of the PRC1 in long noncoding RNA- and H3K27me3-directed gene transcriptional repression.
Insights
Researchers discovered new small molecules that block the chromobox 7 (CBX7) protein, a key player in gene repression. One compound, MS351, effectively reactivates tumor suppressor genes like p16 (INK4a) in cancer cells.
Area of Science:
- Molecular Biology
- Epigenetics
- Drug Discovery
Background:
- Chromobox 7 (CBX7) is part of Polycomb Repressive Complex 1 (PRC1).
- CBX7 represses tumor suppressor genes, such as p16 (INK4a), via long noncoding RNA ANRIL and histone modifications (H3K27me3).
- This repression leads to chromatin compaction at the INK4a/ARF locus.
Purpose of the Study:
- To discover small-molecule antagonists targeting the CBX7 chromodomain (ChD).
- To characterize the mechanism of action for these novel antagonists.
- To evaluate the therapeutic potential of these compounds in cellular models.
Main Methods:
- Structure-guided drug discovery.
- Synthesis and characterization of small-molecule compounds (Class A and Class B).
- X-ray crystallography of the CBX7ChD/MS351 complex.
- Assays to measure gene expression and chromatin status in mouse embryonic stem cells and human prostate cancer PC3 cells.
Main Results:
- Two distinct classes of CBX7ChD antagonists were identified.
- Class A compounds inhibit CBX7ChD/methyl-lysine binding by targeting the H3K27me3 peptide site.
- Class B compound MS351 inhibits H3K27me3 binding when CBX7ChD is bound to RNA, as revealed by crystal structure.
- MS351 effectively induces transcriptional derepression of CBX7 target genes, including p16 (INK4a).
Conclusions:
- MS351 represents a novel class of chromodomain antagonists.
- MS351 selectively targets the biologically active form of CBX7 involved in RNA- and H3K27me3-directed gene repression.
- These findings offer a new therapeutic strategy for cancers driven by aberrant CBX7 activity.
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