Portal de Periódicos da CAPES

Chapter 24 Spleen Tyrosine Kinase (Syk) Biology, Inhibitors and Therapeutic Applications

2007; Elsevier BV; Linguagem: Inglês

10.1016/s0065-7743(07)42024-3

1557-8437

Rajinder Singh, Esteban S. Masuda,

Coagulation, Bradykinin, Polyphosphates, and Angioedema

This chapter discusses the biology of spleen tyrosine kinase (Syk), its inhibitors and therapeutic applications. The most understood function of Syk kinase activity is in ITAM-dependent activation of immunoreceptors, including Fc receptor complexes (FcR) that bind the invariable Fc portion of the different immunoglobulin isotypes and the immunoglobulin B-cell-antigen receptor (BCR) complex. Allergic disorders are characterized by hypersensitive type I immune responses, mediated by immunoglobulin isotype E (IgE), to foreign antigens. Only a handful of pertinent Syk kinase inhibitors have been reported. One such example has been a family of pyrimidine-5-carboxamides. R112 is the first small molecule inhibitor of Syk kinase that has advanced to Phase 2 clinical trials. Compound R112 inhibited Syk kinase with Ki = 0.096 mM, selectively inhibited tryptase release from human mast cells induced by anti-IgE cross-linking, histamine from basophils, and dust mite allergen induced histamine release from human basophils with EC50S = 0.353, 0.28 and 0.49 mM, respectively. One advantage of compound 8 was its rapid onset of action since rapidly effective treatment is highly desirable during an allergic attack.