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

Abstract
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.
AuthorsTetsuo Takayama, Akiko Takaoka, Shuya Takahashi, Akiko Takahashi, Hiroki Umemiya, Masakazu Sato
JournalArzneimittel-Forschung (Arzneimittelforschung) Vol. 60 Issue 5 Pg. 282-5 ( 2010) ISSN: 0004-4172 [Print] Germany
PMID20533766 (Publication Type: Journal Article)
Chemical References
  • Immunosuppressive Agents
  • Indicators and Reagents
  • Protein Kinase Inhibitors
  • Pyrazoles
  • TKM0150
  • Benzodiazepines
  • Protein-Tyrosine Kinases
  • Tacrolimus
  • Picryl Chloride
Topics
  • Animals
  • Benzodiazepines (pharmacokinetics, therapeutic use)
  • Dermatitis, Contact (prevention & control)
  • Female
  • Immunosuppressive Agents (pharmacology)
  • Indicators and Reagents
  • Lymphocyte Culture Test, Mixed
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Picryl Chloride (toxicity)
  • Protein Kinase Inhibitors (pharmacology, therapeutic use)
  • Protein-Tyrosine Kinases (antagonists & inhibitors)
  • Pyrazoles (pharmacokinetics, therapeutic use)
  • Substrate Specificity
  • T-Lymphocytes (drug effects)
  • Tacrolimus (pharmacology)

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