ArticleJournal of the American Chemical Society2014
Mapping the protein interaction landscape for fully functionalized small-molecule probes in human cells.
Article in Journal of the American Chemical Society, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 40 papers.
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Who cites it
40 citing papers in PubMed.
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- Proteome-Wide Fragment-Based Ligand and Target Discovery.Israel journal of chemistry · 2023Article
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- Developing Photoaffinity Probes for Dopamine Receptor DACS chemical neuroscience · 2022Article
- Discovery of compounds that reactivate p53 mutants in vitro and in vivo.Cell chemical biology · 2022Article
- The emerging role of mass spectrometry-based proteomics in drug discovery.Nature reviews. Drug discovery · 2022Review
- Targeting allosteric regulation of cancer metabolism.Nature chemical biology · 2022Review
- Identification of a novel PHGDH covalent inhibitor by chemical proteomics and phenotypic profiling.Acta pharmaceutica Sinica. B · 2022Article
- Identifying novel SMYD3 interactors on the trail of cancer hallmarks.Computational and structural biotechnology journal · 2022Article
- Lessons in Organic Fluorescent Probe Discovery.Chembiochem : a European journal of chemical biology · 2021Review
- Identification of peroxiredoxin 6 as a direct target of withangulatin A by quantitative chemical proteomics in non-small cell lung cancer.Redox biology · 2021Article
- New Trends in Diaziridine Formation and Transformation (a Review).Molecules (Basel, Switzerland) · 2021Review
- Evaluation of fully-functionalized diazirine tags for chemical proteomic applications.Chemical science · 2021Article
- DCAF11 Supports Targeted Protein Degradation by Electrophilic Proteolysis-Targeting Chimeras.Journal of the American Chemical Society · 2021Article
- Modular Approaches to Synthesize Activity- and Affinity-Based Chemical Probes.Frontiers in chemistry · 2021Review
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Authors and funding
4 authors.
Funding
Abstract
Phenotypic screening provides a means to discover small molecules that perturb cell biological processes. Discerning the proteins and biochemical pathways targeted by screening hits, however, remains technically challenging. We recently described the use of small molecules bearing photoreactive groups and latent affinity handles as fully functionalized probes for integrated phenotypic screening and target identification. The general utility of such probes, or, for that matter, any small-molecule screening library, depends on the scope of their protein interactions in cells, a parameter that remains largely unexplored. Here, we describe the synthesis of an ~60-member fully functionalized probe library, prepared from Ugi-azide condensation reactions to impart structural diversity and introduce diazirine and alkyne functionalities for target capture and enrichment, respectively. In-depth mass spectrometry-based analysis revealed a diverse array of probe targets in human cells, including enzymes, channels, adaptor and scaffolding proteins, and proteins of uncharacterized function. For many of these proteins, ligands have not yet been described. Most of the probe-protein interactions showed well-defined structure-activity relationships across the probe library and were blocked by small-molecule competitors in cells. These findings indicate that fully functionalized small molecules canvas diverse segments of the human proteome and hold promise as pharmacological probes of cell biology.
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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.