Background:

Lck Inhibitor is a small-molecule inhibitor of with IC50 value of 7 nM [1].
The lymphocyte specific kinase which expressed in NK cells and T-cells is a member of the Src kinase family. It takes participate in the T-cell receptor (TCR) signal transduction and affects the expression of genes associated with cell proliferation, cytokine release and T-cell survival. Therefore small-molecule inhibitors of Lck with potent activities and bioavailable efficacies have been designed and developed as therapeutic agents for the treatment for T-cell-mediated autoimmune and organ transplant rejection [1].
Lck Inhibitor showed high selectivity against Lck over another Src family kinase Src and the kinases related to inflammation and angiogenesis such as p38 and VEGFR-2 with IC50 values of 0.12, > 10 and 5.1 μM, respectively. Lck Inhibitor also showed more than 1000-fold greater selectivity over CDK, MAPK and the RSK family. In cultured human mixed lymphocytes, the inhibitor significantly suppressed the activation of T-cells with IC50 value of 47 nM. Besides that, this compound inhibited IL-2 secretion induced by T-cell receptor with IC50 value of 0.46 μM. The good potency and selectivity of the Lck Inhibitor were due to the critical aniline side chain within a N-methylpiperazine moiety. It extended to the ATP-binding pocket of the enzyme and formed hydrogen bond interactions with the linker region [1].
In rats model with arthritis induced by the injection of porcine type II collagen, oral administration of the compound dose-dependently suppressed the inflammation with ED50 value of 3.2 mg/kg. While in the adjuvant-induced arthritis model, oral administration of Lck Inhibitor also displayed significant anti- arthritis effects with ED50 value of 24 mg/kg [1].
参考文献:
[1] Martin M W, Newcomb J, Nunes J J, et al. Structure-Based Design of Novel 2-Amino-6-phenyl-pyrimido [5', 4': 5, 6] pyrimido [1, 2-a] benzimidazol-5 (6 H)-ones as Potent and Orally Active Inhibitors of Lymphocyte Specific Kinase (Lck): Synthesis, SAR, and In Vivo Anti-Inflammatory Activity. Journal of medicinal chemistry, 2008, 51(6): 1637-1648.