Discovery of potent and selective SH2 inhibitors of the tyrosine kinase ZAP-70

Journal of Medicinal Chemistry

Volumn 42, Issue 20, 1999, Pages 4088-4098

  Vu, Chi B ^a,b   Corpuz, Evelyn G ^a   Merry, Taylor J ^a   Pradeepan, Selvaluxmi G ^a   Bartlett, Catherine ^a   Bohacek, Regine S ^a   Botfield, Martyn C ^a   Eyermann, Charles J ^a   Lynch, Berkley A ^a   MacNeil, Ian A ^a   Ram, Mary K ^a   Van Schravendijk, Marie Rose ^a   Violette, Shelia ^a   Sawyer, Tomi K ^a  

^a ARIAD PHARMACEUTICALS INC   (United States)

^b BIOGEN   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

1,2,4 OXADIAZOLE DERIVATIVE; PHOSPHOPROTEIN; PROTEIN TYROSINE KINASE; PROTEIN TYROSINE KINASE INHIBITOR; TETRAPEPTIDE;

ARTICLE; CONTROLLED STUDY; DRUG POTENCY; DRUG SELECTIVITY; DRUG SYNTHESIS; IMMUNOSUPPRESSIVE TREATMENT;

ENZYME INHIBITORS; ENZYME PRECURSORS; INTRACELLULAR SIGNALING PEPTIDES AND PROTEINS; MODELS, MOLECULAR; OXADIAZOLES; PROTEIN-TYROSINE KINASES; SRC HOMOLOGY DOMAINS; STRUCTURE-ACTIVITY RELATIONSHIP; ZAP-70 PROTEIN-TYROSINE KINASE;

EID: 0033533792     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm990229t     Document Type: Article

References (57)

1. (a) Weissman, A. M.; Hou, D.; Orloff, D. G.; Modi, W. S.; Seuanez, H.; O'Brien, S. J.; Kluasner, R. D. Molecular cloning and chromosomal localization of the human T cell receptor ζ chain: Distinction from the molecular CDS complex. Proc. Natl. Acad. Sci. U.S.A. 1988, 24, 9709-9713.
2. (b) Strauss, D.; Weiss, A. Genetic evidence for the involvement of the lck tyrosine kinase in signal transduction through the T cell antigen receptor. Cell 1992, 70, 585-593.
3. (a) Reth, M. Antigen receptor tail clue. Nature 1989, 338, 383-384.
4. (b) Iwashima, M.; Irving, B. A.; van Oers, N. S.; Chan, A. C.; Weiss, A. Sequential interactions of the TCR with two distinct cytoplasmic tyrosine kinases. Science 1994, 263, 1136-1139.
5. (a) Straus, D. B.; Weiss, A. The CD3 chains of the T cell antigen receptor associate with the ZAP-70 tyrosine kinase and are tyrosine phosphorylated after receptor stimulation. J. Exp. Med. 1993, 178, 1523-1530.
6. (b) Wange, R. L.; Kong, A.-N. T.; Samelson, L. E. A tyrosine-phosphorylated 70-kDa protein binds a photoaffinity analogue of ATP and associates with both the ζ chain and CD3 components of the activated T cell antigen receptor. J. Biol. Chem. 1992, 267, 11685-11688.
7. (c) van Oers, N. S. C.; Love, P. E.; Shores, E. W.; Weiss, A. Regulation of TCR signal transduction in murine thymocytes by multiple TCR ζ-chain signaling motifs. J. Immunol. 1998, 160, 163-170.
8. (d) Wiest, D. L.; Ashe, J. M.; Abe, R.; Bolen, J. B.; Singer, A. TCR activation of ZAP-70 is impaired in CD4+CD8+ thymocytes as a consequence of intrathymic interactions that diminish available p56lck. Immunity 1996, 4, 495-504.
9. (e) Kersh, E. N.; Shaw, A. S.; Allen, P. M. Fidelity of T cell activation through multistep T cell receptor ζ phosphorylation. Science 1998, 281, 572-575.
10. (a) Wange, R. L.; Malek, S. N.; Desiderio, S.; Samelson, L. E. The tandem SH2 domains of ZAP-70 bind to T cell antigen receptor ζ and CD3e from activated Jurkat T cells. J. Biol. Chem. 1993, 268, 19797-19801.
11. (b) Koyasu, S.; Tse, A. G. D.; Moingeon, P.; Hussey, R. E.; Mildonian, A.; Hannisian, J.; Clayton, K.; Reinherz, E. L. Delineation of a T-cell activation motif required for binding of protein tyrosine kinases containing tandem SH2 domains. Proc. Natl. Acad. Sci. U.S.A. 1994, 91, 6693-6697.
12. 2-TAM ζ3, a novel competitive inhibitor of the binding of ZAP-70 to the T cell antigen receptor, blocks early T cell signaling. J. Biol. Chem. 1995, 270, 944-948.
13. (a) Hivroz, C.; Fischer, A. Multiple roles for ZAP-70. Curr. Biol. 1994, 4, 731-733.
14. (b) Arpaia, E.; Shahar, M.; Dadi, H.; Cohen, A.; Roifman, C. H. Defective T cell receptor signaling in CD8+ thymic selection in humans lacking ZAP-70 kinase. Cell 1994, 76, 947-958.
15. (c) Chan, A. C.; Kadlecek, T. A.; Elder, M. E.; Filipovich, A. H.; Kuo, W. L.; Iwashima, M.; Parslow, T. G.; Weiss, A. ZAP-70 deficiency in an autosomal recessive form of severe combined immunodeficiency. Science 1994, 264, 1599-1601.
16. (d) Elder, M. E.; Lin, D.; Clever, J.; Chan, A. C.; Hope, T. J.; Weiss, A.; Parslow, T. G. Human severe combined immunodeficiency due to a defect in ZAP-70, a T cell tyrosine kinase. Science 1994, 264, 1596-1599.
17. (e) Negishi, I.; Motoyuama, N.; Nakayama, K.I.; Nakayama, K.; Senju, S.; Hatakeyama, S.; Zhang, Q.; Chan, A. C.; Loh, D. Y. Essential role for ZAP-70 in both positive and negative selection of thymocytes. Nature 1995, 376, 435-438.
18. Pawson, T.; Gish, G. D. SH2 and SH3 domains: from structure to function. Cell 1992, 71, 359-363.
19. Cobb, B. S.; Schaller, M. D.; Leu, T. H.; Parsons, J. T. Stable association of pp60src and pp59fyn with the focal adhesion-associated protein tyrosine kinase, pp125FAK. Mol. Cell. Biol. 1994, 14, 147-155.
20. Pellici, G.; Lanfrancone, L.; Grignani F.; McClade, J.; Cavallo, F.; Forni, G.; Nicolleti, I.; Pawson, T.; Pellici, P. A novel transforming protein (SHC) with an SH2 domain is implicated in mitogenic signal transduction. Cell 1992, 70, 93-104.
21. Cooper, J. A.; Howell, B. The when and how of Src regulation. Cell 1993, 73, 1051-1054.
22. Hatada, M. H.; Lu, X.; Laird, E. R.; Green, J.; Morgenstern, J. P.; Lou, M.; Marr, C. S.; Phillips, T. B.; Ram, M. K.; Theriault, K.; Zoller, M. J.; Karas, J. L. Molecular basis for interaction of the protein tyrosine kinase ZAP-70 wtih the T-cell receptor. Nature 1995, 377, 32-38.
23. Grazioli, L.; Germain, V.; Weiss, A.; Acuto, O. Anti-peptide antibodies detect conformational changes of the inter-SH2 domain of ZAP-70 due to binding to the ζ chain and to intramolecular interactions. J. Biol. Chem. 1998, 273, 8916-8921.
24. MacNeil, I. A.; Loiacono, K. A.; Tiong, C. L.; van Schravendijk, M. R.; Ram, M. K.; Minor, C.; Violette, S.; Bartlett, C.; Phillips, T.; Sawyer, T.; Lynch, B. A. Fluorescence polarization based assays for ZAP-70-N,C and Syk-N,C SH2 binding: Screening and selectivity. Manuscript in preparation.
25. Sheets, M. P.; Warrior, U. P.; Yoon, H.; Mollison, K. W.; Djuric, S. W.; Trevillyan, J. M. A high-capacity scintillation proximity assay for the discovery and evaluation of ZAP-70 tandem SH2 domain antagonists. J. Biomol. Screen. 1998, 3, 139-144.
26. 50's that are the average of triplicate measurements. In all cases, ZAP-70 and Syk refer to the tandem SH2 ZAP-70 and Syk.
27. Lynch, B. A. Personal communication.
28. Songyang, Z.; Shoelson, S. E.; Chaudhuri, M.; Gish, G.; Pawson, T.; Haser, W. G.; King, F.; Roberts, T.; Ratnofsky, S.; Lechleider, R. J.; Neel, B. G.; Birge, R. B.; Fajardo, J. E.; Chou, M. M.; Hanafusa, H.; Schaffhausen, B.; Cantley, L. C. SH2 domains recognize specific phosphopeptide sequences. Cell 1993, 72, 767-778.
29. 2 ligand for Src. A large number of tetrapeptide sequences have also been found to be almost as effective. For a discussion on peptide inhibitors of Src SH2, see: Gilmer, T.; Rodriguez, M.; Jordan, S.; Crosby, R.; Alligood, K.; Green, M.; Kimery, M.; Wagner, C.; Kinder, D.; Charifson, P.; Hassel, A. M.; Willard, D.; Luther, M.; Rusnak, D.; Sternbach, D. D.; Mehrotra, M.; Peel, M.; Shampine, L.; Davis, R.; Robbins, J.; Patel, I. R.; Kassel, D.; Burkhart, W.; Moyer, M.; Bradshaw, T.; Berman, J. Peptide inhibitors of Src SH3-SH2-phosphoprotein interactions. J. Biol. Chem. 1994, 269, 31711-31719.
30. Furet, P.; Gay, B.; García-Echeverría, C.; Rahuel, J.; Fretz, H.; Schoepfer, J.; Cavaratti, G. Discovery of 3-aminobenzyloxycarbonyl as an N-terminal group conferring high-affinity to the minimal phosphopeptide sequence recognized by the Grb2-SH2 domain. J. Med. Chem. 1997, 40, 3551-3556.
31. src SH2 domain. J. Am. Chem. Soc. 1997, 119, 12471-12476.
32. c-src SH2 domain. J. Med. Chem. 1998, 41, 1894-1908.
33. (c) For a review on recent advances in Src SH2 inhibitors, see: Sawyer, T. K. Src homology-2-domains: Structure, mechanisms, and drug discovery. Biopolymers 1998, 47, 243-261.
34. (a) Furet, P.; Gay, B.; Cavaratti, G.; Garcia-Echeverria, C.; Rahuel, J.; Schoepfer, J.; Fretz, H. Structure-based design and synthesis of high affinity tripeptide ligands of the Grb2-SH2 domain. J. Med. Chem. 1998, 41, 3442-3449.
35. (b) Schoepfer, J.; Gay, B.; Caravatti, G.; García-Echeverría, C.; Fretz, H.; Rahuel, J.; Furet, P. Structure-based design of peptidomimetic ligands of the Grb2-SH2 domain. Bioorg. Med. Chem. Lett. 1998, 8, 2865-2870.
36. (c) Yao, Z.-J.; King, C. R.; Cao, T.; Kelley, J.; Milne, G. W. A.; Voigt, J. H.; Burke, T. R., Jr. Potent inhibition of Grb2 SH2 domain binding by non-phosphate-containing ligands. J. Med. Chem. 1999, 42, 25-35.
37. (d) Schoepfer, J.; Fretz, H.; Gay, B.; Furet, P.; García-Echeverría, C.; End, N.; Caravatti, G. Highly potent inhibitors of the Grb2-SH2 domain, Bioorg. Med. Chem. Lett. 1999, 9, 221-226.
38. (e) Burke, T. R., Jr.; Luo, J.; Yao, Z.-J.; Gao, Y.; Zhao, H.; Milne, G. W. A.; Guo, R.; Voigt, J. H.; King, C. R.; Yang, D. Monocarboxylic-based phosphotyrosyl mimetics in the design of Grb2 SH2 domain inhibitors. Bioorg. Med. Chem. Lett. 1999, 9, 347-352.
39. (a) Révész, L.; Blum, E.; Manning, U.; Demange, B. J.; Widmer, A.; Zuber, J.-F. Non-peptide ITAM mimics as ZAP-70 antagonists. Bioorg. Med. Chem. Lett. 1997, 7, 2875-2878.
40. (b) Révész, L.; Bonne, F.; Manning, U.; Zuber, J.-F. Solid-phase synthesis of a biased mini tetrapeptoid-library for the discovery of monodentate ITAM mimics as ZAP-70 inhibitors. Bioorg. Med. Chem. Lett. 1998, 8, 405-408.
41. Buchanan, J. L.; Vu, C. B.; Merry, T. J.; Corpuz, E. G.; Pradeepan, S. G.; Mani, U. N.; Yang, M.; Plake, H. R.; Varkhedkar, V. M.; Lynch, B. A.; MacNeil, I. A.; Loiacono, K. A.; Tiong, C. L.; Holt, D. A. Structure-activity relationships of a novel class of Src SH2 inhibitors. Bioorg. Med. Chem. Lett. 1999, 9, 2359-2364.
42. Borg, S.; Estenne-Boutou, G.; Luthman, K.; Csöregh, I.; Hesselink, W.; Hacksell U. Synthesis of 1,2,4-oxadiazole-, 1,3,4-oxadiazole-, and 1,2,4-triazole-derived dipeptidomimetics. J. Org. Chem. 1995, 60, 3112-3120.
43. Füttere, J.; Wong, J.; Grucza, R. A.; Chan, A. C.; Waksman, G. Structural basis for Syk tyrosine kinase ubiquity in signal transduction pathways revealed by the crystal structure of its regulatory SH2 domains bound to a dually phosphorylated ITAM peptide. J. Mol. Biol. 1998, 281, 523-537.
44. 2. Very little selectivity between ZAP-70 and Syk was found with all of these peptides (M. Botfield, J. Green, B. Lynch, personal communication).
45. Chan, A. C.; Iwashima, M.; Turck, C. W.; Weiss, A. ZAP-70: a 70 kd protein-tyrosine kinase that associates with the TCR ζ chain. Cell 1992, 71, 649-662.
46. (a) Hutchcroft, J. E.; Geahlen, R. L.; Deanin, G. G.; Oliver, J. M. Fc∈RI-mediated tyrosine phosphorylation and activation of the 72-kDa protein-tyrosine kinase, PTK72, in RBL-2H3 rat tumor mast cells. Proc. Natl. Acad. Sci. U.S.A. 1992, 89, 9107-9111.
47. syk is activated by wheat germ agglutinin in platelets. Biochem. Biophys. Res. Commun. 1992, 185, 1128-1132.
48. (c) Hutchcroft, J. E.; Harrison, M. L.; Gealen, R. L. Association of the 72 kDa protein-tyrosine kinase PTK72 with the B cell antigen receptor. J. Biol. Chem. 1992, 267, 8613-8619.
49. syk, and paxillin during Fc receptor-mediated phagocytosis in macrophages. J. Biol. Chem. 1994, 269, 3897-3902.
50. (a) Bohacek, R. S.; McMartin, C. Definition and display of steric, hydrophobic, and hydrogen bonding properties of ligand binding sites in proteins using Lee and Richards accessible surface: validation of a high-resolution graphical tool for drug design. J. Med. Chem. 1992, 35, 1671-1684.
51. (b) Bohacek, R. S.; McMartin, C. QXP: powerful, rapid computer algorithms for structure-based drug design. J. Comput.-Aided Mol. Des. 1997, 11, 333-344.
52. SPARTAN 5.1.1, Wavefunction, Inc., 18401 Von Karman Ave, Suite 370, Irvine, CA 92612.
53. 2)-OH. Upon TFA treatment, the phosphate group was unmasked and the BOC group was removed. The resulting amino phosphate derivative was then acylated with the desired acid chloride (see Experimental Section).
54. Hakes, D. J.; Dixon, J. E. New vectors for high level expression of recombinant proteins in bacteria. Anal. Biochem. 1992, 202, 293-298.
55. Lynch, B. A.; Loiacono, K. A.; Tiong, C. L.; Adams, S. E.; MacNeil, I. A. A fluorescence polarization based Src-SH2 binding assay. Anal. Biochem. 1997, 247, 77-82.
56. (a) Fluorescence Polarization Applications Guide; PanVera Corp.: Madison, WI, 1998.
57. (b) Kenakin, T. Pharmacologic Analysis of Drug-Receptor Interaction, 3rd ed.; Raven: New York, 1993; pp 255-258.