BMS-509744

BMS-509744 is a selective inhibitor of ITK with IC50 value of 15 nM [1].
ITK (IL-2-inducible T cell kinase) is an enzyme and plays an important role in T cell receptor signaling. It has been reported that ITK involves in the Th2-mediated inflammatory process and thus be regarded as a promising target for Th2-mediated inflammatory/immunosuppressive diseases treatment, such as asthma, rhinitis, allergies and atopic dermatitis [2].
BMS-509744 is a potent ITK inhibitor and is different from the reported ITK inhibitor RO5191614. When tested with human and murine cells, administration of BMS-509744 reduced TCR-induced functions by functioning on PLCgamma1 tyrosine phosphorylation, calcium mobilization, IL-2 secretion and T-cell proliferation [2]. In wild-typr HIV1 infected cells, BMS-509744 treatment blocked its infectivity and replication by inhibiting ITK, while has no effect on Nef-defective HIV1 infected cells [3].
In mouse model of ovalbuim-induced allergy/asthma, administration of BMS-509744 suppressed the production of IL-2 and significantly diminished lung inflammation by inhibiting ITK activity [2].
References:
[1].Kutach, A.K., 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(2): p. 154-63.
[2].Lin, T.A., et al., Selective Itk inhibitors block T-cell activation and murine lung inflammation. Biochemistry, 2004. 43(34): p. 11056-62.
[3].Tarafdar, S., J.A. Poe, and T.E. Smithgall, The accessory factor Nef links HIV-1 to Tec/Btk kinases in an Src homology 3 domain-dependent manner. J Biol Chem, 2014. 289(22): p. 15718-28.