Boron‐Based Inhibitors of Acyl Protein Thioesterases 1 and 2

Ras proteins are of importance in cell proliferation, and hence their mutated forms play causative roles in many kinds of cancer in different tissues. Inhibition of the Ras‐depalmitoylating enzyme acyl protein thioesterases APT1 and ‐2 is a new approach to modulating the Ras cycle. Here we present boronic and borinic acid derivatives as a new class of potent and nontoxic APT inhibitors. These compounds were detected by extensive library screening using chemical arrays and turned out to inhibit human APT1 and ‐2 in a competitive mode. Furthermore, one of the molecules was demonstrated to inhibit Erk1/2 phosphorylation significantly.

[1]  Steven J Brown,et al.  Confirming target engagement for reversible inhibitors in vivo by kinetically tuned activity-based probes. , 2012, Journal of the American Chemical Society.

[2]  P. Bastiaens,et al.  Chemical‐Biological Exploration of the Limits of the Ras De‐ and Repalmitoylating Machinery , 2012, Chembiochem : a European journal of chemical biology.

[3]  H. Goto,et al.  Discovery of Novel Antiviral Agents Directed Against the Influenza A Virus Nucleoprotein , 2012 .

[4]  M. Chudziński,et al.  Borinic Acids: A Neglected Class of Organoboron Compounds for Recognition of Diols in Aqueous Solution , 2011 .

[5]  P. Bastiaens,et al.  Development of highly potent inhibitors of the Ras-targeting human acyl protein thioesterases based on substrate similarity design. , 2011, Angewandte Chemie.

[6]  I. Vetter,et al.  Identification of acyl protein thioesterases 1 and 2 as the cellular targets of the Ras-signaling modulators palmostatin B and M. , 2011, Angewandte Chemie.

[7]  F. Dekker,et al.  Small molecule inhibition of protein depalmitoylation as a new approach towards downregulation of oncogenic Ras signalling. , 2011, Bioorganic & medicinal chemistry.

[8]  H. Osada.  Introduction of New Tools for Chemical Biology Research on Microbial Metabolites , 2010, Bioscience, biotechnology, and biochemistry.

[9]  Stefan Wetzel,et al.  Small-molecule inhibition of APT1 affects Ras localization and signaling. , 2010, Nature chemical biology.

[10]  D. Hall,et al.  Mild silver(I)-mediated regioselective iodination and bromination of arylboronic acids. , 2010, Organic letters.

[11]  P. Bastiaens,et al.  The Palmitoylation Machinery Is a Spatially Organizing System for Peripheral Membrane Proteins , 2010, Cell.

[12]  K. Mikoshiba,et al.  Synthesis of bisboron compounds and their strong inhibitory activity on store-operated calcium entry. , 2010, Bioorganic & medicinal chemistry letters.

[13]  Hongtao Jia,et al.  Ras-MAPK pathway as a therapeutic target in cancer--emphasis on bladder cancer. , 2009, Recent patents on anti-cancer drug discovery.

[14]  B. Shoichet,et al.  Structure-based optimization of cephalothin-analogue boronic acids as beta-lactamase inhibitors. , 2008, Bioorganic & medicinal chemistry.

[15]  G. Basso,et al.  Bortezomib-mediated 26S proteasome inhibition causes cell-cycle arrest and induces apoptosis in CD-30+ anaplastic large cell lymphoma , 2007, Leukemia.

[16]  S. Yokoyama,et al.  Photo-cross-linked small-molecule microarrays as chemical genomic tools for dissecting protein-ligand interactions. , 2006, Chemistry, an Asian journal.

[17]  S. Benkovic,et al.  Identification of a novel boron-containing antibacterial agent (AN0128) with anti-inflammatory activity, for the potential treatment of cutaneous diseases. , 2006, Bioorganic & medicinal chemistry letters.

[18]  R. Goody,et al.  Lipidated ras and rab peptides and proteins--synthesis, structure, and function. , 2006, Angewandte Chemie.

[19]  H. Waldmann,et al.  Lipidierte Ras‐ und Rab‐Peptide und ‐Proteine: Synthese, Struktur und Funktion , 2006 .

[20]  Herbert Waldmann,et al.  Therapeutic intervention based on protein prenylation and associated modifications , 2006, Nature chemical biology.

[21]  Kazuki Inamori,et al.  SPR imaging of photo-cross-linked small-molecule arrays on gold. , 2006, Analytical chemistry.

[22]  John A Timbrell,et al.  In vitro cytotoxicity assays: comparison of LDH, neutral red, MTT and protein assay in hepatoma cell lines following exposure to cadmium chloride. , 2006, Toxicology letters.

[23]  H. Waldmann,et al.  Solid-phase synthesis of lipidated peptides. , 2005, Journal of the American Chemical Society.

[24]  Herbert Waldmann,et al.  An Acylation Cycle Regulates Localization and Activity of Palmitoylated Ras Isoforms , 2005, Science.

[25]  Gregory A Petsko,et al.  2.4 A resolution crystal structure of the prototypical hormone-processing protease Kex2 in complex with an Ala-Lys-Arg boronic acid inhibitor. , 2003, Biochemistry.

[26]  M. Mareel,et al.  The new sulindac derivative IND 12 reverses Ras-induced cell transformation. , 2002, Cancer research.

[27]  A. Adjei,et al.  Blocking oncogenic Ras signaling for cancer therapy. , 2001, Journal of the National Cancer Institute.

[28]  Herbert Waldmann,et al.  Bioorganic synthesis of lipid-modified proteins for the study of signal transduction , 2000, Nature.

[29]  S. D. Kimball,et al.  Thrombin active site inhibitors. , 1995, Bioorganic & medicinal chemistry.

[30]  Bradley D. Smith,et al.  DIPHENYLBORINIC ACID IS A STRONG INHIBITOR OF SERINE PROTEASES , 1994 .

[31]  A. Kleinfeld,et al.  A fluorescently labeled intestinal fatty acid binding protein. Interactions with fatty acids and its use in monitoring free fatty acids. , 1992, The Journal of biological chemistry.

[32]  J. B. Jones,et al.  Probing the specificity of the S1 binding site of subtilisin Carlsberg with boronic acids. , 1991, Biochemical and Biophysical Research Communications - BBRC.

[33]  C. W. Garner.  Boronic acid inhibitors of porcine pancreatic lipase. , 1980, The Journal of biological chemistry.

[34]  R. Seger,et al.  Determination of ERK activity: anti-phospho-ERK antibodies and in vitro phosphorylation. , 2010, Methods in molecular biology.

[35]  A. Prongay,et al.  Potent inhibitors of HCV-NS3 protease derived from boronic acids. , 2009, Bioorganic & medicinal chemistry letters.

[36]  B. Gallwitz.  Sitagliptin: profile of a novel DPP-4 inhibitor for the treatment of type 2 diabetes (update). , 2007, Drugs of today.

[37]  R. Lindquist,et al.  Inhibition of subtilisin by boronic acids, potential analogs of tetrahedral reaction intermediates. , 1974, Archives of biochemistry and biophysics.

[38]  H. J. Roth,et al.  Synthese phenyl‐ und thienylsubstituierter Boron‐ und Borinsäuren ) , 1964 .