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Protein-protein interaction: Is this a “druggable”target? CAD - R&D Dr.ssa G.Gallo 20-12-2006
Protein-protein interaction (PPI) ,[object Object],[object Object],[object Object],[object Object]
Why ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],Arkin M.R.&Wells J.A.  Nature reviews 2004, 3, 301
Antibodies ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],Small molecules inhibitors
[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],Why not Fry D.C. Biopolymers (2006) 84, 535-552
Proposed solutions ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
Strategies ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
Therapeutic target ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
From peptide to peptidomimetic ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
Integrins ,[object Object],[object Object],[object Object],[object Object],Xiao T. et al. Nature 2004, 32, 59 a : low affinity in a bent conformation b : intermediate affinity in an extended  form and closed headpiece  c : High affinity in an extended form and  open headpiece with exposure of ligand  induced binding sites (LIBS)
Antitrombotic agents ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],Scarborough R. M.&Gretler D.D. J.Med. Chem. 2000, 3, 353
Linear peptides (RGD >300   M; RGDS 26   M) Cyclic peptides Platelet aggregation  test  IC 50 =32   M IC 50 =72 nM IC 50  = 97 nM selective 1985- 1999 Searle, SK, Roche, Fujisawa, Rhone-Poulenc ,  Merck, Genentech, COR ther. IC 50 =26 nM selective IC 50 = 46 nM Selective Intravenous and oral  administration
[object Object],Platelet aggregation test  IC 50 =140 nM; selective Fibrinogen: KQAGDV
Subset of a corporate library (Merck) containing amine and  carboxylic acid functionalities at distance 10-20  Å IC 50 = 11 nM Selective N-  -sulfonamide  “ exosite” binding Platelet aggregation test  IC 50 = 27   M Hit compound Hartman G.D. et al. J.Med. Chem. 1992, 35, 4640 IC 50 = 260 nM
[object Object]
Magenta    subunit Cyano    subunit Xiao T. et al. Nature 2004, 32, 59
Table 1. Parenteral GPIIb-IIIa Antagonists Table 2. Clinical Status of Oral GPIIb-IIIa Antagonists
 
[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],Fragment-based approach
Tilley J.W. Et al JACS 1997, 119, 7589 Arkin M.R. et al. PNAS 2003, 100, 1603 Roche 24 Mimicking of  R36 and E29 on IL-2R  and bindind of E62 and K43 on IL-2  Biaryl alchene group in a deep groove
Raimundo B.C. et al. J.Med.Chem. 2004, 47, 3111 Sunesis – Tethering approach
60 nM
[object Object],[object Object],Computational approaches Core 2,4-dihydroxybenzene not interacting IC 50  = 770   M Sarabu R et al. Drug. Des. Discovery 1998, 15, 191 2,4-dihydroxybenzene mimicking F46 IC 50  < 10   M
Computational approaches ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],Wang J-L. et al. PNAS 2000, 97, 7124 HA14-1: IC 50  = 9   M
Covalent modificators ,[object Object],[object Object],[object Object],[object Object],[object Object],Zutshi R.&Chmielewski J. Bioorg.Med.Chem.Lett. 2000, 10, 1901 K inact  = 3.7  M
Antibody as template ,[object Object],[object Object],[object Object],Rationally designed anti-HER2 peptide mimetic Trastuzumab CDR3 mimetic AHNP: FCDGFYACYMDV Park B.W. et al. Nat. Biotechnol. 2000, vol. 18 pag. 194
Allosteric modulation ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],McMillan K. et al. PNAS 2000, 97, 1506
Protein stabilization Microtubule stabilizing drugs: Taxol Downing K.H. Emerging Ther.  Targets 2000, 4, 219 Stabilized mutant p53 in  DNA binding domain: Pfizer: CP-31398 Foster B.A. et al. Science 1999, 286, 2507

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Protein-protein interaction

  • 1. Protein-protein interaction: Is this a “druggable”target? CAD - R&D Dr.ssa G.Gallo 20-12-2006
  • 2.
  • 3.
  • 4.
  • 5.
  • 6.
  • 7.
  • 8.
  • 9.
  • 10.
  • 11.
  • 12. Linear peptides (RGD >300  M; RGDS 26  M) Cyclic peptides Platelet aggregation test IC 50 =32  M IC 50 =72 nM IC 50 = 97 nM selective 1985- 1999 Searle, SK, Roche, Fujisawa, Rhone-Poulenc , Merck, Genentech, COR ther. IC 50 =26 nM selective IC 50 = 46 nM Selective Intravenous and oral administration
  • 13.
  • 14. Subset of a corporate library (Merck) containing amine and carboxylic acid functionalities at distance 10-20 Å IC 50 = 11 nM Selective N-  -sulfonamide “ exosite” binding Platelet aggregation test IC 50 = 27  M Hit compound Hartman G.D. et al. J.Med. Chem. 1992, 35, 4640 IC 50 = 260 nM
  • 15.
  • 16. Magenta  subunit Cyano  subunit Xiao T. et al. Nature 2004, 32, 59
  • 17. Table 1. Parenteral GPIIb-IIIa Antagonists Table 2. Clinical Status of Oral GPIIb-IIIa Antagonists
  • 18.  
  • 19.
  • 20. Tilley J.W. Et al JACS 1997, 119, 7589 Arkin M.R. et al. PNAS 2003, 100, 1603 Roche 24 Mimicking of R36 and E29 on IL-2R  and bindind of E62 and K43 on IL-2 Biaryl alchene group in a deep groove
  • 21. Raimundo B.C. et al. J.Med.Chem. 2004, 47, 3111 Sunesis – Tethering approach
  • 22. 60 nM
  • 23.
  • 24.
  • 25.
  • 26.
  • 27.
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