Cited by 11014-3-3 protein interactionsProtein Kinase Regulation and GTPase SignalingProtein Structure and Dynamics

Discovery and structural characterization of a small molecule 14-3-3 protein-protein interaction inhibitor

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Zhao, Jing, Du, Yuhong, Horton, John R., Upadhyay, Anup K., Lou, Bin, Bai, Yan, Zhang, Xing, Du, Lupei +7 more·2011·Proceedings of the National Academy of Sciences

Abstract

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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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;
Venue
Proceedings of the National Academy of Sciences
Published
2011-09-09
Volume
108
Issue
39
Pages
16212-16216
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
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
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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