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(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 14-3-3ζ 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: Department of Pharmacology, Emory UniversitySchool of Medicine, Atlanta, GA 30322, USA.
authors: Jing
authors: J
authors: Zhao
authors: Yuhong
authors: Y
authors: Du
authors: John R
authors: JR
authors: Horton
authors: Anup K
authors: AK
authors: Upadhyay
authors: Bin
authors: B
authors: Lou
authors: Yan
authors: Y
authors: Bai
authors: Xing
authors: X
authors: Zhang
authors: Lupei
authors: L
authors: Du
authors: Minyong
authors: M
authors: Li
authors: Binghe
authors: B
authors: Wang
authors: Lixin
authors: L
authors: Zhang
authors: Joseph T
authors: JT
authors: Barbieri
authors: Fadlo R
authors: FR
authors: Khuri
authors: Xiaodong
authors: X
authors: Cheng
authors: Haian
authors: H
authors: Fu
mesh_terms: D048948:14-3-3 Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D018360:Crystallography, X-Ray; D004797:Enzyme-Linked Immunosorbent Assay; D005454:Fluorescence Polarization; D008958:Models, Molecular; D011485:Protein Binding; D011487:Protein Conformation; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
chemical_list: D048948:14-3-3 Proteins