Discovery of Fluoromethylketone-Based Peptidomimetics as Covalent ATG4B (Autophagin-1) Inhibitors.

ATG4B or autophagin-1 is a cysteine protease that cleaves ATG8 family proteins. ATG4B plays essential roles in the autophagosome formation and the autophagy pathway. Herein we disclose the design and structural modifications of a series of fluoromethylketone (FMK)-based peptidomimetics as highly potent ATG4B inhibitors. Their structure-activity relationship (SAR) and protease selectivity are also discussed.

[1]  B. Kuhn,et al.  Identification of New ATG4B Inhibitors Based on a Novel High-Throughput Screening Platform , 2017, SLAS discovery : advancing life sciences R & D.

[2]  L. Ouyang,et al.  Unraveling the roles of Atg4 proteases from autophagy modulation to targeted cancer therapy. , 2016, Cancer letters.

[3]  John Calvin Reed,et al.  ATG4B (Autophagin-1) Phosphorylation Modulates Autophagy* , 2015, The Journal of Biological Chemistry.

[4]  A. Chaudhary,et al.  Targeting autophagy to overcome drug resistance in cancer therapy. , 2015, Future medicinal chemistry.

[5]  Satoru Kobayashi,et al.  Choose Delicately and Reuse Adequately: The Newly Revealed Process of Autophagy. , 2015, Biological & pharmaceutical bulletin.

[6]  Xiao-Ming Yin,et al.  A novel ATG4B antagonist inhibits autophagy and has a negative impact on osteosarcoma tumors , 2014, Autophagy.

[7]  R. Young,et al.  Development of fluorescent substrates and assays for the key autophagy-related cysteine protease enzyme, ATG4B. , 2014, Assay and drug development technologies.

[8]  K. Blakely,et al.  Context-dependent role of ATG4B as target for autophagy inhibition in prostate cancer therapy. , 2013, Biochemical and biophysical research communications.

[9]  W. Hait,et al.  Therapeutic Targeting of Autophagy in Disease: Biology and Pharmacology , 2013, Pharmacological Reviews.

[10]  F. Diederich,et al.  Efficient Stacking on Protein Amide Fragments , 2013, ChemMedChem.

[11]  D. Rubinsztein,et al.  Autophagy modulation as a potential therapeutic target for diverse diseases , 2012, Nature Reviews Drug Discovery.

[12]  John Calvin Reed,et al.  High-Throughput Fluorescence Assay for Small-Molecule Inhibitors of Autophagins/Atg4 , 2011, Journal of biomolecular screening.

[13]  Hiroyuki Kumeta,et al.  The structure of Atg4B–LC3 complex reveals the mechanism of LC3 processing and delipidation during autophagy , 2009, The EMBO journal.

[14]  B. Seed,et al.  Quantitation of autophagy by luciferase release assay , 2008, Autophagy.

[15]  Paul R. Gerber,et al.  MAB, a generally applicable molecular force field for structure modelling in medicinal chemistry , 1995, J. Comput. Aided Mol. Des..