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

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{sub 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{zeta} 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.

Authors:
; ; ; ; ; ; ; ; ; ; ; ; ; ;  [1];  [2];  [2];  [2]
  1. (Emory-MED)
  2. (
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
NIHOTHER U.S. STATES
OSTI Identifier:
1040909
Resource Type:
Journal Article
Journal Name:
Proc. Natl. Acad. Sci. USA
Additional Journal Information:
Journal Volume: 108; Journal Issue: (39) ; 09, 2011; Journal ID: ISSN 0027-8424
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES; BIOLOGY; CRYSTAL STRUCTURE; DISEASES; DOUBLE BONDS; DRUGS; INACTIVATION; LYSINE; NEOPLASMS; PROTEINS; SCREENS; TARGETS

Citation Formats

Zhao, Jing, Du, Yuhong, Horton, John R., Upadhyay, Anup K., Lou, Bin, Bai, Yan, Zhang, Xing, Du, Lupei, Li, Minyong, Wang, Binghe, Zhang, Lixin, Barbieri, Joseph T., Khuri, Fadlo R., Cheng, Xiaodong, Fu, Haian, GSU), MCW), and Chinese Aca. Sci.). Discovery and structural characterization of a small molecule 14-3-3 protein-protein interaction inhibitor. United States: N. p., 2013. Web. doi:10.1073/pnas.1100012108.
Zhao, Jing, Du, Yuhong, Horton, John R., Upadhyay, Anup K., Lou, Bin, Bai, Yan, Zhang, Xing, Du, Lupei, Li, Minyong, Wang, Binghe, Zhang, Lixin, Barbieri, Joseph T., Khuri, Fadlo R., Cheng, Xiaodong, Fu, Haian, GSU), MCW), & Chinese Aca. Sci.). Discovery and structural characterization of a small molecule 14-3-3 protein-protein interaction inhibitor. United States. doi:10.1073/pnas.1100012108.
Zhao, Jing, Du, Yuhong, Horton, John R., Upadhyay, Anup K., Lou, Bin, Bai, Yan, Zhang, Xing, Du, Lupei, Li, Minyong, Wang, Binghe, Zhang, Lixin, Barbieri, Joseph T., Khuri, Fadlo R., Cheng, Xiaodong, Fu, Haian, GSU), MCW), and Chinese Aca. Sci.). Thu . "Discovery and structural characterization of a small molecule 14-3-3 protein-protein interaction inhibitor". United States. doi:10.1073/pnas.1100012108.
@article{osti_1040909,
title = {Discovery and structural characterization of a small molecule 14-3-3 protein-protein interaction inhibitor},
author = {Zhao, Jing and Du, Yuhong and Horton, John R. and Upadhyay, Anup K. and Lou, Bin and Bai, Yan and Zhang, Xing and Du, Lupei and Li, Minyong and Wang, Binghe and Zhang, Lixin and Barbieri, Joseph T. and Khuri, Fadlo R. and Cheng, Xiaodong and Fu, Haian and GSU) and MCW) and Chinese Aca. Sci.)},
abstractNote = {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{sub 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{zeta} 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.},
doi = {10.1073/pnas.1100012108},
journal = {Proc. Natl. Acad. Sci. USA},
issn = {0027-8424},
number = (39) ; 09, 2011,
volume = 108,
place = {United States},
year = {2013},
month = {2}
}