Advances in the design of ITK inhibitors

Expert Opinion on Drug Discovery

Volumn 8, Issue 4, 2013, Pages 369-381

  Charrier, Jean Damien ^a   Knegtel, Ronald M A ^a  

^a VERTEX PHARMACEUTICALS   (United States)

Author keywords

Drug discovery; IL 2 inducible T cell kinase (ITK); Immune mediated disorders; Kinase inhibitor; T cell signaling

Indexed keywords

BMS 509744; GAMMA INTERFERON; IMMUNOSUPPRESSIVE AGENT; INTERLEUKIN 10; INTERLEUKIN 13; INTERLEUKIN 2 INDUCIBLE T CELL KINASE; INTERLEUKIN 2 INDUCIBLE T CELL KINASE INHIBITOR; INTERLEUKIN 4; INTERLEUKIN 5; PHOSPHOTRANSFERASE INHIBITOR; PROTEIN TYROSINE KINASE; STAUROSPORINE; T LYMPHOCYTE RECEPTOR; TUMOR NECROSIS FACTOR ALPHA; UNCLASSIFIED DRUG;

B LYMPHOCYTE; CD4+ T LYMPHOCYTE; CRYSTAL STRUCTURE; CYTOKINE PRODUCTION; DRUG BIOAVAILABILITY; DRUG CONFORMATION; DRUG DESIGN; DRUG STRUCTURE; DRUG TRANSFORMATION; ENZYME ACTIVITY; ENZYME CONFORMATION; ENZYME INHIBITION; GENE INACTIVATION; HIGH THROUGHPUT SCREENING; HUMAN; HYDROGEN BOND; IC 50; IMMUNE RESPONSE; IMMUNOPATHOLOGY; IMMUNOSUPPRESSIVE TREATMENT; LIGAND BINDING; NONHUMAN; PHENOTYPE; PRIORITY JOURNAL; PROTEIN PHOSPHORYLATION; REVIEW; SIGNAL TRANSDUCTION; T LYMPHOCYTE SUBPOPULATION; TH1 CELL; TH2 CELL;

ANIMALS; DRUG DESIGN; ENZYME INHIBITORS; HUMANS; MICE; PROTEIN-TYROSINE KINASES; SIGNAL TRANSDUCTION; T-LYMPHOCYTES;

EID: 84875399635     PISSN: 17460441     EISSN: 1746045X     Source Type: Journal    
DOI: 10.1517/17460441.2013.769520     Document Type: Review

References (56)

1. Berg LJ, Finkelstein LD, Lucas JA, et al. Tec family kinases in T lymphocyte development and function. Annu Rev Immunol 2005;23:549-600
2. Shan X, Wange RL. Itk/Emt/Tsk activation in response to CD3 cross-linking in Jurkat T cells requires ZAP-70 and Lat and is independent of membrane recruitment. J Biol Chem 1999;274:29323-30
3. Bunnell SC, Diehn M, Yaffe MB, et al. Biochemical interactions integrating Itk with the T cell receptor-initiated signaling cascade. J Biol Chem 2000;275:2219-30
4. Perez-Villar JJ, Whitney GS, Sitnick MT, et al. Phosphorylation of the linker for activation of T-cells by Itk promotes recruitment of Vav. Biochemistry 2002;41:10732-40
5. Ching KA, Grasis JA, Tailor P, et al. TCR/CD3-induced activation and binding of Emt/Itk to linker of activated T cell complexes: requirement for the Src homology 2 domain. J Immunol 2000;165:256-62
6. August A, Sadra A, Dupont B, et al. Src-induced activation of inducible T cell kinase (ITK) requires phosphatidylinositol 3-kinase activity and the Pleckstrin homology domain of inducible T cell kinase. Proc Natl Acad Sci USA 1997;94:11227-32
7. Heyeck SD, Wilcox HM, Bunnell SC, et al. Lck phosphorylates the activation loop tyrosine of the Itk kinase domain and activates Itk kinase activity. J Biol Chem 1997;272:25401-8
8. Wilcox HM, Berg LJ. Itk phosphorylation sites are required for functional activity in primary T cells. J Biol Chem 2003;278:37112-21
9. Lin X, O'Mahoney A, Mu Y, et al. Protein kinase C-theta participates in NF-kappaB activation induced by CD3-CD28 costimulation through selective activation of IkappaB kinase beta. Mol Cell Biol 2000;20:2933-40
10. Feske S. Calcium signalling in lymphocyte activation and disease. Nat Rev Immunol 2007;7:690-702
11. Grasis JA, Browne CD, Tsoukas CD. Inducible T cell tyrosine kinase regulates actin-dependent cytoskeletal events induced by the T cell antigen receptor. J Immunol 2003;170:3971-6
12. Labno CM, Lewis CM, You D, et al. Itk functions to control actin polymerization at the immune synapse through localized activation of Cdc42 and WASP. Curr Biol 2003;13:1619-24
13. Finkelstein LD, Shimizu Y, Schwartzberg PL. Tec kinases regulate TCR-mediated recruitment of signaling molecules and integrin-dependent cell adhesion. J Immunol 2005;175:5923-30
14. Dombroski D, Houghtling RA, Labno CM, et al. Kinase-independent functions for Itk in TCR-induced regulation of Vav and the actin cytoskeleton. J Immunol 2005;174:1385-92
15. Kaur M, Bahia MS, Silakari O. Inhibitors of interleukin-2 T-cell kinase as potential therapeutic candidates for the treatment of various inflammatory disease conditions. Eur J Pharm Sci 2012;47:574-88
16. Fowell DJ, Shinkai K, Liao XC, et al. Impaired NFATc translocation and failure of Th2 development in ITK-deficient CD4+ T cells. Immunity 1999;11:399-409
17. Schaeffer EM, Yap GS, Lewis CM, et al. Mutation of Tec family kinases alters T helper cell differentiation. Nat Immunol 2001;2:1183-8
18. Debnath J, Chamorro M, Czar MJ, et al. rlk/TXK encodes two forms of a novel cysteine string tyrosine kinase activated by Src family kinases. Mol Cell Biol 1999;19:1498-507
19. Gibson S, August A, Kawakami Y, et al. The EMT/ITK/TSK (EMT) tyrosine kinase is activated during TCR signaling: LCK is required for optimal activation of EMT. J Immunol 1996;156:2716-22
20. Yang WC, Ghiotto M, Barbarat B, et al. The role of Tec protein-tyrosine kinase in T cell signaling. J Biol Chem 1999;274:607-17
21. Liu KQ, Bunnell SC, Gurniak CB, et al. T cell receptor-initiated calcium release is uncoupled from capacitative calcium entry in ITK-deficient T cells. J Exp Med 1998;187:1721-7
22. Liao XC, Littman DR. Altered T cell receptor signaling and disrupted T cell development in mice lacking ITK. Immunity 1995;3:757-69
23. Schaeffer EM, Broussard C, Debnath J, et al. Tec family kinases modulate thresholds for thymocyte development and selection. J Exp Med 2000;192:987-1000
24. Lucas JA, Atherly LO, Berg LJ, et al. The absence of ITK inhibits positive selection without changing lineage commitment. J Immunol 2002;168:6142-51
25. Mueller C, August A. Attenuation of immunological symptoms of allergic asthma in mice lacking the tyrosine kinase ITK. J Immunol 2003;170:5056-63
26. Miller AT, Wilcox HM, Lai Z, et al. Signaling through ITK promotes T helper 2 differentiation via negative regulation of T-bet. Immunity 2004;21:67-80
27. Bachmann MF, Littman DR, Liao XC, et al. Antiviral immune responses in ITK-deficient mice. J Virol 1997;71:7253-7
28. Schaeffer EM, Debnath J, Yap G, et al. Requirement for Tec kinases Rlk and ITK in T cell receptor signaling and immunity. Science 1999;284:638-41
29. Brown K, Long JM, Vial SCM, et al. Crystal structures of interleukin-2 tyrosine kinase and their implications for the design of selective inhibitors. J Biol Chem 2004;279:18727-32
30. Berman HM, Westbrook J, Feng Z, et al. The protein data bank. Nucleic Acids Res 2000;28:235-42
31. Bristol-Myers Squibb Pharmaceutical. Preparation of thiazolyl inhibitors of Tec family tyrosine kinases. WO2002050071; 2002
32. Das J, Liu C, Moquin RV, et al. Discovery and SAR of 2-amino-5- [(thiomethyl)aryl]thiazoles as potent and selective ITK inhibitors. Bioorg Med Chem Lett 2006;16:2411-15
33. Das J, Furch JA, Liu C, et al. Discovery and SAR of 2-amino-5-(thioaryl) thiazoles as potent and selective ITK inhibitors. Bioorg Med Chem Lett 2006;16:3706-12
34. Lin TA, McIntyre KW, Das J, et al. Selective ITK inhibitors block T-cell activation and murine lung inflammation. Biochemistry 2004;43:11056-62
35. Snow RJ, Abeywardane A, Campbell S, et al. Hit-to-lead studies on benzimidazole inhibitors of ITK: Discovery of a novel class of kinase inhibitors. Bioorg Med Chem Lett 2007;17:3660-5
36. Moriarty KJ, Winters M, Qiao L, et al. ITK kinase inhibitors: initial efforts to improve the metabolical stability and the cell activity of the benzimidazole lead. Bioorg Med Chem Lett 2008;18:5537-40
37. Moriarty KJ, Takahashi H, Pullen SS, et al. Discovery, SAR and X-ray of 1H-benzimidazole-5-carboxylic acid cyclohexyl-methyl-amides as inhibitors of inducible T-cell kinase (ITK). Bioorg Med Chem Lett 2008;18:5545-9
38. Lo HY, Bentzien J, Fleck RW, et al. 2-Aminobenzimidazoles as potent ITK antagonists: trans-stilbene-like moieties targeting the kinase specificity pocket. Bioorg Med Chem Lett 2008;18:6218-21
39. Lo HY, Bentzien J, White A, et al. 2-Aminobenzimidazoles as potent ITK antagonists: de novo design of a pyrrole system targeting additional hydrogen bonding interaction. Tetahedron Lett 2008;49:7337-40
40. Cook BN, Bentzien J, White A, et al. Discovery of potent inhibitors of interleukin-2 inducible T-cell kinase (ITK) through structure-based drug design. Bioorg Med Chem Lett 2009;19:773-7
41. Riether D, Zindell R, Kowalski A, et al. 5-Aminomethylbenzimdazoles as potent ITK antagonists. Bioorg Med Chem Lett 2009;19:1588-91
42. Boehringer Ingelheim Pharmaceuticals. Preparation of thiophene-2- carboxylic acid (1H-benzimidazol-2 yl)amides and related compounds as inhibitors of the Tec kinase ITK (interleukin-2-inducible T-cell kinase) useful for treating of inflammation, immune diseases and allergic disorders. WO 2005079791; 2005
43. Winters MP, Robinson DJ, Khine HH, et al. 5-Aminomethyl-1H-benzimidazoles as orally active inhibitors of inducible T-cell kinase (ITK). Bioorg Med Chem Lett 2008;18:5541-4
44. Charrier JD, Miller A, Kay DP, et al. Discovery and structure-activity relationship of 3-aminopyrid-2-ones as potent and selective interleukin-2 inducible T-cell kinase (ITK) inhibitors. J Med Chem 2011;54:2341-50
45. Knegtel RMA, Robinson DD. A role for hydration in interleukin-2 inducible T cell kinase (ITK) selectivity. Mol Inf 2011;30:950-9
46. Vertex Pharmaceuticals. Preparation of pyrid-2-ones useful as inhibitors of Tec family protein kinases for the treatment of inflammatory, proliferative and immunologically-mediated diseases. WO2006065946; 2006
47. McLean LR, Zhang Y, Zaidi N, et al. Z-ray crystallographic structure-based design of selective thienopyrazole inhibitors for interleukin-2 inducible tyrosine kinase. Bioorg Med Chem Lett 2012;22:3296-300
48. Sanofi. Preparation of thienopyrazoles as inhibitors of interleukin-2 inducible tyrosine kinase for treating diseases involving overproduction of Th2 cytokine like asthma. WO2005026175; 2005
49. Herdemann M, Heit I, Bosch FU, et al. Identification of potent ITK inhibitors through focused compound library design including structural information. Bioorg Med Chem Lett 2010;20:6998-7003
50. Herdemann M, Weber A, Jonveaux J, et al. Optimisation of ITK inhibitors through successive iterative design cycles. Bioorg Med Chem Lett 2011;21:1852-6
51. Von Bonin A, Rausch A, Mengel A, et al. Inhibition of the IL-2-inducible tyrosine kinase (ITK) activity: a new concept for the therapy of inflammatory skin diseases. Exp Dermatol 2011;20:41-7
52. Guo W, Liu R, Ono Y, et al. Molecular characteristics of CTA056, a novel ITK inhibitor which selectivity targets malignant T cells and modulates oncomirs. Mol Pharm 2012;82:938-47
53. Lo HY. ITK inhibitors: a patent review. Expert Opin Ther Pat 2010;20:459-69
54. Kutach AK, Villasenor AG, Lam D, et al. Crystal structures of IL-2-inducible T cell kinase complexed with inhibitors: insights into rational drug design and activity regulation. Chem Biol Drug Des 2010;76:154-63
55. Xu W, Doshi A, Lei M, et al. Crystal structures of c-Src reveal features of its autoinhibitory mechanism. Mol Cell 1999;3:629-38
56. Cheetham GMT. Novel protein kinases and molecular mechanisms of autoinhibition. Curr Opin Struct Biol 2004;14:700-5