ArticleACS chemical biology2015
Identification of a fragment-like small molecule ligand for the methyl-lysine binding protein, 53BP1.
Article in ACS chemical biology, 2015. 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, 62 citations in OpenAlex.
- Expansion of DNA-Encoded Library Hits Using Generative Chemistry and Ultra-Large Compound Catalogs.bioRxiv : the preprint server for biology · 2025Article
- Review
- Exploring the Ligandability of 53BP1 through Fragment-Based Approaches.ACS medicinal chemistry letters · 2025Article
- BAHCC1 binds H4K20me1 to facilitate the MCM complex loading and DNA replication.Nature communications · 2025Article
- Epigenetics-targeted drugs: current paradigms and future challenges.Signal transduction and targeted therapy · 2024Review
- Discovery of a 53BP1 Small Molecule Antagonist Using a Focused DNA-Encoded Library Screen.Journal of medicinal chemistry · 2023Article
- An autoinhibited state of 53BP1 revealed by small molecule antagonists and protein engineering.Nature communications · 2023Article
- Pharmacological perturbation of the phase-separating protein SMNDC1.Nature communications · 2023Article
- Multivalent binding of the hub protein LC8 at a newly discovered site in 53BP1.Biophysical journal · 2022Article
- Targeting protein-protein interactions in the DNA damage response pathways for cancer chemotherapy.RSC chemical biology · 2021Review
- Inhibition of DNA Repair in Cancer Therapy: Toward a Multi-Target Approach.International journal of molecular sciences · 2020Review
- The Chemical Biology of Reversible Lysine Post-translational Modifications.Cell chemical biology · 2020Review
- Targeting epigenetic protein-protein interactions with small-molecule inhibitors.Future medicinal chemistry · 2020Review
- Using Chemical Epigenetics to Target Cancer.Molecular cell · 2020Review
- Small Molecules Targeting the Specific Domains of Histone-Mark Readers in Cancer Therapy.Molecules (Basel, Switzerland) · 2020Review
- Targeting non-bromodomain chromatin readers.Nature structural & molecular biology · 2019Review
- Targeting protein methylation: from chemical tools to precision medicines.Cellular and molecular life sciences : CMLS · 2019Review
- Phosphorylation promotes activation-induced cytidine deaminase activity at the Myc oncogene.The Journal of experimental medicine · 2017Article
- Chemical modulators for epigenome reader domains as emerging epigenetic therapies for cancer and inflammation.Current opinion in chemical biology · 2017Review
- Developing Spindlin1 small-molecule inhibitors by using protein microarrays.Nature chemical biology · 2017Article
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Authors and funding
17 authors at 5 institutions in 2 countries.
Funding
Abstract
Improving our understanding of the role of chromatin regulators in the initiation, development, and suppression of cancer and other devastating diseases is critical, as they are integral players in regulating DNA integrity and gene expression. Developing small molecule inhibitors for this target class with cellular activity is a crucial step toward elucidating their specific functions. We specifically targeted the DNA damage response protein, 53BP1, which uses its tandem tudor domain to recognize histone H4 dimethylated on lysine 20 (H4K20me2), a modification related to double-strand DNA breaks. Through a cross-screening approach, we identified UNC2170 (1) as a micromolar ligand of 53BP1, which demonstrates at least 17-fold selectivity for 53BP1 as compared to other methyl-lysine (Kme) binding proteins tested. Structural studies revealed that the tert-butyl amine of UNC2170 anchors the compound in the methyl-lysine (Kme) binding pocket of 53BP1, making it competitive with endogenous Kme substrates. X-ray crystallography also demonstrated that UNC2170 binds at the interface of two tudor domains of a 53BP1 dimer. Importantly, this compound functions as a 53BP1 antagonist in cellular lysates and shows cellular activity by suppressing class switch recombination, a process which requires a functional 53BP1 tudor domain. These results demonstrate that UNC2170 is a functionally active, fragment-like ligand for 53BP1.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.