Hiroki Umemiya

Pyrrole derivatives as potent inhibitors of lymphocyte-specific kinase: Structure, synthesis, and SAR

We have described the synthesis, enzyme inhibitory activity, structure-activity relationships, and proposed binding mode of a novel series of pyrrole derivatives as lymphocyte-specific kinase (Lck) inhibitors. The most potent analogs exhibited good enzyme inhibitory activity (IC(50)s <10nM) for Lck kinase inhibition.

Ring-fused pyrazole derivatives as potent inhibitors of lymphocyte-specific kinase (Lck): Structure, synthesis, and SAR.

We have identified a novel series of ring-fused pyrazole derivatives as lymphocyte-specific kinase (Lck) inhibitors. The most potent analogs exhibited good enzyme inhibitory activity (IC(50)s <1nM) as well as excellent cellular activity against mixed lymphocyte reaction (MLR) (IC(50)s <1nM).

Effects of the novel and potent lymphocyte-specific protein tyrosine kinase inhibitor TKM0150 on mixed lymphocyte reaction and contact hypersensitivity in mice.

Lymphocyte-specific protein tyrosine kinase (Lck) plays a critical role in T cell activation. In the present study, the effect of a newly synthesized small molecule compound, 7-[2-(dimethylamino)ethoxy]-2-(4-phenoxyphenyl)-9,10-dihydro-4H- pyrazolo[5,1-b] [1,3]benzodiazepine-3-carboxamide (TKM0150) on Lck activity was investigated. TKM0150 inhibited Lck with an 1C50 value of 0.7 nM. To evaluate if TKM0150 is a specific inhibitor of Lck, the activity against several Src (Proto-oncogene tyrosine-protein kinase Src) and non-Src family kinases were assayed. TKM150 inhibited Src family kinases, Src and Csk (c-Src kinase) (with IC50 values of 0.6 nM and 1.7 nM, respectively) as well as Fyn (p59-Fyn) and Lyn (tyrosine-protein kinase Lyn) at a dose of 1 microM; however, it did not inhibit kinase which is a non-Src family kinase in the tyrosine kinase (TK) group, nor kinases in other groups. Then, the anti-inflammtory potential of TKM0150 was evaluated by known experimental models. TKM0150 inhibited the murine mixed lymphocyte reaction (MLR) in vitro with an IC50 value of 0.7 nM, and 2,4,6-trinitro-1-chlorobenzene-induced contact hypersensitivity in vivo at a dose of 0.3 and 1% w/v administered topically. These results indicate that TKM0150 is a specific inhibitor of Lck/Src kinase and can block T cell-mediated responses in vitro and in vivo. Accordingly, TKM0150 would be expected as a drug candidate for treating T cell-mediated disorders including atopic dermatitis.