ArticleCombinatorial chemistry & high throughput screening2012
A high throughput scintillation proximity imaging assay for protein methyltransferases.
Article in Combinatorial chemistry & high throughput screening, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed, 30 citations in OpenAlex.
- Elevated glucose levels increase vascular calcification risk by disrupting extracellular pyrophosphate metabolism.Cardiovascular diabetology · 2024Article
- Chemical probes and methods for the study of protein arginine methylation.RSC chemical biology · 2023Review
- Methylation of dual-specificity phosphatase 4 controls cell differentiation.Cell reports · 2021Article
- Direct High-Throughput Screening Assay for mRNA Cap Guanine-N7 Methyltransferase Activity.Chemistry (Weinheim an der Bergstrasse, Germany) · 2020Article
- Methionine Adenosyltransferase Engineering to Enable Bioorthogonal Platforms for AdoMet-Utilizing Enzymes.ACS chemical biology · 2020Article
- A chemical probe of CARM1 alters epigenetic plasticity against breast cancer cell invasion.eLife · 2019Article
- Targeted drug combination therapy design based on driver genes.Oncotarget · 2019Article
- Article
- Kinetic isotope effects reveal early transition state of protein lysine methyltransferase SET8.Proceedings of the National Academy of Sciences of the United States of America · 2016Article
- Design, synthesis, and protein methyltransferase activity of a unique set of constrained amine containing compounds.Bioorganic & medicinal chemistry letters · 2016Article
- Small Molecule Inhibitors of Protein Arginine Methyltransferases.Expert opinion on investigational drugs · 2016Review
- Small-molecule inhibitors of SETD8 with cellular activity.ACS chemical biology · 2014Article
- Chemical & RNAi screening at MSKCC: a collaborative platform to discover & repurpose drugs to fight disease.Combinatorial chemistry & high throughput screening · 2014Article
- Assay development for histone methyltransferases.Assay and drug development technologies · 2013Article
- Rapid and sensitive method to identify Mycobacterium avium subsp. paratuberculosis in cow's milk by DNA methylase genotyping.Applied and environmental microbiology · 2013Article
- Profiling protein methylation with cofactor analog containing terminal alkyne functionality.Current protocols in chemical biology · 2013Article
- A high-content biosensor-based screen identifies cell-permeable activators and inhibitors of EGFR function: implications in drug discovery.Journal of biomolecular screening · 2012Article
Corrections and comments
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Authors and funding
8 authors at 1 institution in 1 country.
Funding
Abstract
Protein methyltransferases (PMTs) orchestrate epigenetic modifications through post-translational methylation of various protein substrates including histones. Since dysregulation of this process is widely implicated in many cancers, it is of pertinent interest to screen inhibitors of PMTs, as they offer novel target-based opportunities to discover small molecules with potential chemotherapeutic use. We have thus developed an enzymatic screening strategy, which can be adapted to scintillation proximity imaging assay (SPIA) format, to identify these inhibitors. We took advantage of S-adenosyl-L-[3H-methyl]-methionine availability and monitored the enzymatically catalyzed [3H]-methyl addition on lysine residues of biotinylated peptide substrates. The radiolabeled peptides were subsequently captured by streptavidin coated SPA imaging PS beads. We applied this strategy to four PMTs: SET7/9, SET8, SETD2, and EuHMTase1, and optimized assay conditions to achieve Z' values ranging from 0.48 to 0.91. The robust performance of this SPIA for the four PMTs was validated in a pilot screen of approximately 7,000 compounds. We identified 80 cumulative hits across the four targets. NF279, a suramin analogue, was found to specifically inhibit SET7/9 and SETD2 with IC50 values of 1.9 and 1.1 μM, respectively. Another identified compound, Merbromin, a topical antiseptic, was classified as a pan-active inhibitor of the four PMTs. These findings demonstrate that our proposed SPIA strategy is generic for multiple PMTs and can be successfully implemented to identify novel and specific inhibitors of PMTs. The specific PMT inhibitors may constitute a new class of anti-proliferative agents for potential therapeutic use.
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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.