Substituted 1,4‐Benzodiazepine‐2,5‐diones as α‐Helix Mimetic Antagonists of the HDM2‐p53 Protein–Protein Interaction

Small molecule antagonists of protein–protein interactions represent a particular challenge for pharmaceutical discovery. One approach to finding molecules that can disrupt these interactions is to seek mimics of common protein structure motifs. We present an analysis of how molecules based on the 1,4‐benzodiazepine‐2,5‐dione scaffold serve to mimic the side‐chains presented by the hydrophobic face of two turns of an α‐helix derived from the tumor suppressor protein p53, and thus antagonize the HDM2‐p53 protein–protein binding interaction.

[1]  Min Wu,et al.  The initial evaluation of non-peptidic small-molecule HDM2 inhibitors based on p53-HDM2 complex structure. , 2002, Cancer letters.

[2]  D. Rich,et al.  Peptidomimetic design. , 1998, Current opinion in chemical biology.

[3]  John A. Robinson,et al.  Using a beta-hairpin to mimic an alpha-helix: cyclic peptidomimetic inhibitors of the p53-HDM2 protein-protein interaction. , 2004, Angewandte Chemie.

[4]  D. Rich,et al.  Designing non-peptide peptidomimetics in the 21st century: inhibitors targeting conformational ensembles. , 2002, Journal of medicinal chemistry.

[5]  Sarah A. Teichmann,et al.  Principles of protein-protein interactions , 2002, ECCB.

[6]  C. Papageorgiou,et al.  A non-peptide ligand for the somatostatin receptor having a benzodiazepinone structure , 1996 .

[7]  C. Prives.  Signaling to p53 Breaking the MDM2–p53 Circuit , 1998, Cell.

[8]  R. Strausberg,et al.  From Knowing to Controlling: A Path from Genomics to Drugs Using Small Molecule Probes , 2003, Science.

[9]  P. Chène.  Inhibiting the p53–MDM2 interaction: an important target for cancer therapy , 2003, Nature Reviews Cancer.

[10]  Jorge Becerril,et al.  Design and application of an alpha-helix-mimetic scaffold based on an oligoamide-foldamer strategy: antagonism of the Bak BH3/Bcl-xL complex. , 2003, Angewandte Chemie.

[11]  P. Furet,et al.  Discovery of potent antagonists of the interaction between human double minute 2 and tumor suppressor p53. , 2000, Journal of medicinal chemistry.

[12]  P. Toogood.  Inhibition of protein-protein association by small molecules: approaches and progress. , 2002, Journal of medicinal chemistry.

[13]  T. Berg.  Modulation of protein-protein interactions with small organic molecules. , 2003, Angewandte Chemie.

[14]  A. Hamilton,et al.  Toward proteomimetics: terphenyl derivatives as structural and functional mimics of extended regions of an alpha-helix. , 2001, Journal of the American Chemical Society.

[15]  Thomas Rawson,et al.  From Peptide to Non-Peptide. 2. The de Novo Design of Potent, Non-peptidal Inhibitors of Platelet Aggregation Based on a Benzodiazepinedione Scaffold , 1994 .

[16]  Donald J Abraham,et al.  A nonpeptidic sulfonamide inhibits the p53-mdm2 interaction and activates p53-dependent transcription in mdm2-overexpressing cells. , 2004, Journal of medicinal chemistry.

[17]  D. Lane,et al.  Identification of novel mdm2 binding peptides by phage display. , 1996, Oncogene.

[18]  Andrew D. Hamilton,et al.  Development of a Potent Bcl-xL Antagonist Based on α-Helix Mimicry , 2002 .

[19]  S F Howard,et al.  Molecular characterization of the hdm2-p53 interaction. , 1997, Journal of molecular biology.

[20]  D. Fabbro,et al.  A small synthetic peptide, which inhibits the p53-hdm2 interaction, stimulates the p53 pathway in tumour cell lines. , 2000, Journal of molecular biology.

[21]  A. Levine,et al.  Structure of the MDM2 Oncoprotein Bound to the p53 Tumor Suppressor Transactivation Domain , 1996, Science.

[22]  Maxwell D Cummings,et al.  1,4-Benzodiazepine-2,5-diones as small molecule antagonists of the HDM2-p53 interaction: discovery and SAR. , 2005, Bioorganic & medicinal chemistry letters.

[23]  D. Eisenberg.  Proteins. Structures and molecular properties, T.E. Creighton. W. H. Freeman and Company, New York (1984), 515, $36.95 , 1985 .

[24]  S. Sharma,et al.  Protein-protein interactions: lessons learned. , 2002, Current medicinal chemistry. Anti-cancer agents.

[25]  C. Renner,et al.  Chalcone derivatives antagonize interactions between the human oncoprotein MDM2 and p53. , 2001, Biochemistry.

[26]  Michelle R. Arkin,et al.  Small-molecule inhibitors of protein–protein interactions: progressing towards the dream , 2004, Nature Reviews Drug Discovery.

[27]  M. Shair.  A closer view of an oncoprotein-tumor suppressor interaction. , 1997, Chemistry & biology.

[28]  M L Connolly,et al.  The molecular surface package. , 1993, Journal of molecular graphics.

[29]  A G Cochran,et al.  Antagonists of protein-protein interactions. , 2000, Chemistry & biology.

[30]  Edgar Jacoby,et al.  Biphenyls as potential mimetics of protein α-helix , 2002 .

[31]  H. Carlson,et al.  Computational studies and peptidomimetic design for the human p53–MDM2 complex , 2004, Proteins.

[32]  Peter Ertl,et al.  Design and synthesis of pyrrolidine-5,5-trans-lactams (5-oxohexahydropyrrolo[3,2-b]pyrroles) as novel mechanism-based inhibitors of human cytomegalovirus protease. 2. Potency and chirality. , 2002, Journal of medicinal chemistry.

[33]  L. Vassilev,et al.  In Vivo Activation of the p53 Pathway by Small-Molecule Antagonists of MDM2 , 2004, Science.

[34]  Joshua A. Kritzer,et al.  Helical β-Peptide Inhibitors of the p53-hDM2 Interaction , 2004 .

[35]  Maxwell D Cummings,et al.  Discovery and cocrystal structure of benzodiazepinedione HDM2 antagonists that activate p53 in cells. , 2005, Journal of medicinal chemistry.

[36]  D. Kahne,et al.  Use of a retroinverso p53 peptide as an inhibitor of MDM2. , 2004, Journal of the American Chemical Society.

[37]  T. N. Bhat,et al.  The Protein Data Bank , 2000, Nucleic Acids Res..

[38]  Oliver Zerbe,et al.  Using a β‐Hairpin To Mimic an α‐Helix: Cyclic Peptidomimetic Inhibitors of the p53–HDM2 Protein–Protein Interaction , 2004 .

[39]  W. C. Ripka,et al.  Protein β-turn mimetics II: Design, synthesis, and evaluation in the cyclic peptide gramicidin S , 1993 .

[40]  A. Levinson,et al.  Benzodiazepine peptidomimetics: potent inhibitors of Ras farnesylation in animal cells. , 1993, Science.