Chemical tools to expand the ligandable proteome: Diversity-oriented synthesis-based photoreactive stereoprobes
Open accessPublished version of a preprint
Abstract
Chemical proteomics enables the global analysis of small molecule-protein interactions in native biological systems and has emerged as a versatile approach for ligand discovery. The range of small molecules explored by chemical proteomics has, however, remained limited. Here, we describe a diversity-oriented synthesis (DOS)-inspired library of stereochemically defined compounds bearing diazirine and alkyne units for UV light-induced covalent modification and click chemistry enrichment of interacting proteins, respectively. We find that these "photo-stereoprobes" interact in a stereoselective manner with hundreds of proteins from various structural and functional classes in human cells and demonstrate that these interactions can form the basis for high-throughput screening-compatible NanoBRET assays. Integrated phenotypic screening and chemical proteomics identified photo-stereoprobes that modulate autophagy by engaging the mitochondrial serine protease CLPP. Our findings show the utility of DOS-inspired photo-stereoprobes for expanding the ligandable proteome, furnishing target engagement assays, and facilitating the discovery and characterization of bioactive compounds in phenotypic screens.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Autophagy in infection, inflammation and immunity
Deretic, V., Saitoh, T., & Akira, S. (2013) · Nature Reviews Immunology · doi:10.1038/nri3532 · Cited by 1,919 · see citing works
How were new medicines discovered?
Swinney, D. C., & Anthony, J. (2011) · Nature Reviews Drug Discovery · doi:10.1038/nrd3480 · Cited by 1,812 · see citing works
Twenty years on: the impact of fragments on drug discovery
Erlanson, D. A., Fesik, S. W., Hubbard, R. E., Jahnke, W., & Jhoti, H. (2016) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2016.109 · Cited by 1,000 · see citing works
Proteome-wide covalent ligand discovery in native biological systems
Backus, K. M., Correia, B. E., Lum, K. M., Forli, S., Horning, B. D., González-Páez, G. E., Chatterjee, S., Lanning, B. R., Teijaro, J. R., Olson, A. J., et al. (2016) · Nature · doi:10.1038/nature18002 · Cited by 940 · see citing works
Self-citationDrugging the ‘undruggable’ cancer targets
Dang, C. V., Reddy, E. P., Shokat, K. M., & Soucek, L. (2017) · Nature Reviews Cancer · doi:10.1038/nrc.2017.36 · Cited by 927 · see citing works
How many human proteoforms are there?
Aebersold, R., Agar, J. N., Amster, I. J., Baker, M. S., Bertozzi, C. R., Boja, E. S., Costello, C. E., Cravatt, B. F., Fenselau, C., Garcia, B. A., et al. (2018) · Nature Chemical Biology · doi:10.1038/nchembio.2576 · Cited by 907 · see citing works
Self-citationLigand and Target Discovery by Fragment-Based Screening in Human Cells
Parker, C. G., Galmozzi, A., Wang, Y., Correia, B. E., Sasaki, K., Joslyn, C. M., Kim, A. S., Cavallaro, C. L., Lawrence, R. M., Johnson, S. R., et al. (2017) · Cell · doi:10.1016/j.cell.2016.12.029 · Cited by 439 · see citing works
Self-citationUnexplored therapeutic opportunities in the human genome
Oprea, T. I., Bologa, C. G., Brunak, S., Campbell, A., Gan, G. N., Gaulton, A., Gomez, S. M., Guha, R., Hersey, A., Holmes, J., et al. (2018) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2018.14 · Cited by 378 · see citing works
Screen for Chemical Modulators of Autophagy Reveals Novel Therapeutic Inhibitors of mTORC1 Signaling
Balgi, A. D., Fonseca, B. D., Donohue, E., Tsang, T. C. F., Lajoie, P., Proud, C. G., Nabi, I. R., & Roberge, M. (2009) · PLoS ONE · doi:10.1371/journal.pone.0007124 · Cited by 344 · see citing works
Chemical Proteomics Identifies Druggable Vulnerabilities in a Genetically Defined Cancer
Bar-Peled, L., Kemper, E. K., Suciu, R. M., Vinogradova, E. V., Backus, K. M., Horning, B. D., Paul, T. A., Ichu, T.-A., Svensson, R. U., Olucha, J., et al. (2017) · Cell · doi:10.1016/j.cell.2017.08.051 · Cited by 262 · see citing works
Self-citationHow Chemoproteomics Can Enable Drug Discovery and Development
Moellering, R. E., & Cravatt, B. F. (2012) · Chemistry & Biology · doi:10.1016/j.chembiol.2012.01.001 · Cited by 182 · see citing works
Self-citation
Flagged first, then by citations
- Authors
- Ogasawara, D., Konrad, D. B., Tan, Z. Y., Carey, K. L., Luo, J., Won, S. J., Li, H., Carter, T. R., DeMeester, K. E., Njomen, E., Schreiber, S. L., Xavier, R. J., Melillo, B., & Cravatt, B. F.
- Affiliations
- Scripps Research Institute (US)
- Broad Institute (US)
- Corresponding author
- Ogasawara, Daisuke
- Melillo, Bruno
- Cravatt, Benjamin F.
- ORCID
- Venue
- Cell Chemical Biology
- Publisher
- Elsevier BV
- Published
- 2024-12
- Volume
- 31
- Issue
- 12
- Pages
- 2138-2155.e32
- ISSN
- 2451-9448 (ISSN-L)
- 2451-9456
- PMC
- PMC11837778
- OpenAlex
- W4404375241
- Cited by
- 31
- References
- 11
- Citations by year
- 2026: 16 · 2025: 10 · 2024: 5
- FWCI
- 4.32
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 383 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Cell chemical biology (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Discovery Research Portal (University of Dundee) (publishedVersion)
- PubMed Central (submittedVersion)
- Funders
- National Cancer Institute
- National Institutes of Health (P30 DK043351)
- Howard Hughes Medical Institute (GT15176)
- Bristol-Myers Squibb
- National Institute of Neurological Disorders and Stroke (U19 AI142784)
- Japan Society for the Promotion of Science
- Leona M. and Harry B. Helmsley Charitable Trust
- Topics
- Physical Sciences › Chemistry › Organic Chemistry › Click Chemistry and Applications
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chemical Synthesis and Analysis
- Physical Sciences › Chemistry › Spectroscopy › Advanced Proteomics Techniques and Applications
- Keywords
- chemoproteomics, diversity-oriented synthesis, diazirine, alkynes, click chemistry, protein-protein interaction, NanoBRET, autophagy, ClpP, mitochondrial serine protease, phenotypic screening, target engagement
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
