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Discovery and structural characterization of a small molecule 14-3-3 protein-protein interaction inhibitor
Open accessAbstract
The 14-3-3 family of phosphoserine/threonine-recognition proteins engage multiple nodes in signaling networks that control diverse physiological and pathophysiological functions and have emerged as promising therapeutic targets for such diseases as cancer and neurodegenerative disorders. Thus, small molecule modulators of 14-3-3 are much needed agents for chemical biology investigations and therapeutic development. To analyze 14-3-3 function and modulate its activity, we conducted a chemical screen and identified 4-[(2Z)-2-[4-formyl-6-methyl-5-oxo-3-(phosphonatooxymethyl)pyridin-2-ylidene]hydrazinyl]benzoate as a 14-3-3 inhibitor, which we termed FOBISIN (FOurteen-three-three BInding Small molecule INhibitor) 101. FOBISIN101 effectively blocked the binding of 14-3-3 with Raf-1 and proline-rich AKT substrate, 40 kD a and neutralized the ability of 14-3-3 to activate exoenzyme S ADP-ribosyltransferase. To provide a mechanistic basis for 14-3-3 inhibition, the crystal structure of 14-3-3 ζ in complex with FOBISIN101 was solved. Unexpectedly, the double bond linking the pyridoxal-phosphate and benzoate moieties was reduced by X-rays to create a covalent linkage of the pyridoxal-phosphate moiety to lysine 120 in the binding groove of 14-3-3, leading to persistent 14-3-3 inactivation. We suggest that FOBISIN101-like molecules could be developed as an entirely unique class of 14-3-3 inhibitors, which may serve as radiation-triggered therapeutic agents for the treatment of 14-3-3-mediated diseases, such as cancer.
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Metadata
- Authors
- Zhao, J., Du, Y., Horton, J. R., Upadhyay, A. K., Lou, B., Bai, Y., Zhang, X., Du, L., Li, M., Wang, B., Zhang, L., Barbieri, J. T., Khuri, F. R., Cheng, X., & Fu, H.
- Affiliations
- Air Force Medical University (CN)
- Emory University (US)
- Biochemistry; and
- Departments of Pharmacology;
- Department of Chemistry, Georgia State University, Atlanta, GA 30302;
- Georgia State University (US)
- Chinese Academy of Sciences (CN)
- Medical College of Wisconsin (US)
- Hematology and Medical Oncology;
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2011-09-09
- Volume
- 108
- Issue
- 39
- Pages
- 16212-16216
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3182712
- OpenAlex
- W2156331971
- Cited by
- 105
- References
- 38
- Citations by year
- 2026: 1 · 2025: 4 · 2024: 10 · 2023: 2 · 2022: 2 · 2021: 2 · 2020: 10 · 2019: 3 · 2018: 3 · 2017: 9 · 2016: 7 · 2015: 13 · 2014: 6 · 2013: 15 · 2012: 15
- FWCI
- 5.06
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Emory University
- School of Medicine, Emory University
- National Cancer Institute (P01CA116676)
- National Institute of General Medical Sciences (GM092035, GM068680, RC1GM092035, R01GM068680)
- National Institute of Allergy and Infectious Diseases (AI-030162, R01AI030162)
- Argonne National Laboratory
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › 14-3-3 protein interactions
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Keywords
- 14-3-3 proteins, protein-protein interaction inhibitors, small molecule inhibitors, Raf-1, PRAS40, cancer therapy
- MeSH terms
- Animals, Chlorocebus aethiops, Enzyme-Linked Immunosorbent Assay, Fluorescence Polarization, Models, Molecular, Protein Binding, Protein Conformation, Crystallography, X-Ray, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization, COS Cells, 14-3-3 Proteins
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