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.
Medicinal Research Laboratories, Taisho Pharmaceutical Co., Ltd., Saitama, Japan. tetsuo.takayama@po.rd.taisho.co.jp
Tetsuo
T
Takayama
Akiko
A
Takaoka
Shuya
S
Takahashi
Akiko
A
Takahashi
Hiroki
H
Umemiya
Masakazu
M
Sato
D000818:Animals; D001569:Benzodiazepines / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D003877:Dermatitis, Contact / Q000517:prevention & control*; D005260:Female; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007202:Indicators and Reagents; D007959:Lymphocyte Culture Test, Mixed; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D010853:Picryl Chloride / Q000633:toxicity; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011720:Pyrazoles / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D013379:Substrate Specificity; D013601:T-Lymphocytes / Q000187:drug effects; D016559:Tacrolimus / Q000494:pharmacology
D007166:Immunosuppressive Agents; D007202:Indicators and Reagents; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; C550659:TKM0150; D001569:Benzodiazepines; D011505:Protein-Tyrosine Kinases; D016559:Tacrolimus; D010853:Picryl Chloride