ArticleACS chemical biology2016
Chromodomain Ligand Optimization via Target-Class Directed Combinatorial Repurposing.
Article in ACS chemical biology, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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Who cites it
27 citing papers in PubMed.
- Structural landscape of H3K27me3 recognition by protein domains and their potential for inhibition.The Journal of biological chemistry · 2026Review
- Influence of the Electrostatic Tuning of Alkyl and Benzyl Groups on Cation-π Interactions in Histone Reader Proteins and β-Hairpin Peptides.Biochemistry · 2026Article
- Expansion of DNA-Encoded Library Hits Using Generative Chemistry and Ultra-Large Compound Catalogs.bioRxiv : the preprint server for biology · 2025Article
- Epigenetic reader chromodomain as a potential therapeutic target.RSC chemical biology · 2025Review
- Discovery of CHD1 Antagonists for PTEN-Deficient Prostate Cancer.Journal of medicinal chemistry · 2024Article
- Discovery of a 53BP1 Small Molecule Antagonist Using a Focused DNA-Encoded Library Screen.Journal of medicinal chemistry · 2023Article
- Chemical tools targeting readers of lysine methylation.Current opinion in chemical biology · 2023Review
- Targeting Protein-Protein Interfaces with Peptides: The Contribution of Chemical Combinatorial Peptide Library Approaches.International journal of molecular sciences · 2023Review
- Lineage-coupled clonal capture identifies clonal evolution mechanisms and vulnerabilities of BRAFCell discovery · 2022Article
- Covalent labeling of a chromatin reader domain using proximity-reactive cyclic peptides.Chemical science · 2022Article
- Cdyl Deficiency Brakes Neuronal Excitability and Nociception through Promoting Kcnb1 Transcription in Peripheral Sensory Neurons.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2022Article
- Systematic Variation of Both the Aromatic Cage and Dialkyllysine via GCE-SAR Reveal Mechanistic Insights in CBX5 Reader Protein Binding.Journal of medicinal chemistry · 2022Article
- Discovery of Potent Peptidomimetic Antagonists for Heterochromatin Protein 1 Family Proteins.ACS omega · 2022Article
- AD Informer Set: Chemical tools to facilitate Alzheimer's disease drug discovery.Alzheimer's & dementia (New York, N. Y.) · 2022Article
- Article
- A Peptidomimetic Ligand Targeting the Chromodomain of MPP8 Reveals HRP2's Association with the HUSH Complex.ACS chemical biology · 2021Article
- Polycomb Repressive Complex 2 Modulation through the Development of EZH2-EED Interaction Inhibitors and EED Binders.Journal of medicinal chemistry · 2021Review
- Improved methods for targeting epigenetic reader domains of acetylated and methylated lysine.Current opinion in chemical biology · 2021Review
- Discovery of an H3K36me3-Derived Peptidomimetic Ligand with Enhanced Affinity for Plant Homeodomain Finger Protein 1 (PHF1).Journal of medicinal chemistry · 2021Article
- Getting a handle on chemical probes of chomatin readers.Future medicinal chemistry · 2021Article
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8 authors.
Funding
Abstract
Efforts to develop strategies for small-molecule chemical probe discovery against the readers of the methyl-lysine (Kme) post-translational modification have been met with limited success. Targeted disruption of these protein-protein interactions via peptidomimetic inhibitor optimization is a promising alternative to small-molecule hit discovery; however, recognition of identical peptide motifs by multiple Kme reader proteins presents a unique challenge in the development of selective Kme reader chemical probes. These selectivity challenges are exemplified by the Polycomb repressive complex 1 (PRC1) chemical probe, UNC3866, which demonstrates submicromolar off-target affinity toward the non-PRC1 chromodomains CDYL2 and CDYL. Moreover, since peptidomimetics are challenging subjects for structure-activity relationship (SAR) studies, traditional optimization of UNC3866 would prove costly and time-consuming. Herein, we report a broadly applicable strategy for the affinity-based, target-class screening of chromodomains via the repurposing of UNC3866 in an efficient, combinatorial peptide library. A first-generation library yielded UNC4991, a UNC3866 analogue that exhibits a distinct selectivity profile while maintaining submicromolar affinity toward the CDYL chromodomains. Additionally, in vitro pull-down experiments from HeLa nuclear lysates further demonstrate the selectivity and utility of this compound for future elucidation of CDYL protein function.
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