Target Validation Information
Target ID T79798
Target Name MAP kinase p38
Target Type
Clinical Trial
Drug Potency against Target BIRB 796 Drug Info IC50 = 0.1 nM [552495]
VX-745 Drug Info IC50 = 0.8 nM [552773]
ML-3403 Drug Info IC50 = 990 nM [526668]
ML-3163 Drug Info IC50 = 880 nM [526355]
RWJ-68354 Drug Info IC50 = 7 nM [526530]
ML-3375 Drug Info IC50 = 1200 nM [526668]
Talmapimod Drug Info IC50 = 9 nM [552972]
VK-19911 Drug Info IC50 = 71 nM [526904]
Action against Disease Model VX-745 VX-745 induces modest growth inhibition of MM.1S, RPMI8226, and U266 cell lines in a dose-dependent fashion, with inhibitory concentration of 50% (IC50) of 10 M as assessed by MTT assay. [552312] Drug Info
The Effect of Target Knockout, Knockdown or Genetic Variations Mice lacking p38delta gene exhibited a marked resistance to development of 7,12-dimethylbenz(a)anthracene/12-O-tetra-decanoylphorbol-13-acetate-induced skin papillomas,with increased latency and greatly reduced incidence, multiplicity, and size of t uMors compared with wild-type mice. Our data suggest that the underlying mechanism for reduced susceptibility to skin carcinogenesis in p38delta-null mice involves a defect in proliferative response associated with aberrant signaling through the two major transformation-promoting pathways:extracellular signal-regulated kinase1/2-activator protein and signal transducer and activator of transcription.These findings strongly suggest an in vivo role for p38D in promoting cell proliferation and t uMor development in epidermisand may have therapeutic implication for skin cancer. [552495]
References
Ref 552495A small molecule-kinase interaction map for clinical kinase inhibitors. Nat Biotechnol. 2005 Mar;23(3):329-36. Epub 2005 Feb 13.
Ref 552773A quantitative analysis of kinase inhibitor selectivity. Nat Biotechnol. 2008 Jan;26(1):127-32. doi: 10.1038/nbt1358.
Ref 552312Targeting p38 MAPK inhibits multiple myeloma cell growth in the bone marrow milieu. Blood. 2003 Jan 15;101(2):703-5. Epub 2002 Sep 5.
Ref 526668J Med Chem. 2003 Jul 17;46(15):3230-44.Novel substituted pyridinyl imidazoles as potent anticytokine agents with low activity against hepatic cytochrome P450 enzymes.
Ref 526355J Med Chem. 2002 Jun 20;45(13):2733-40.From imidazoles to pyrimidines: new inhibitors of cytokine release.
Ref 526530Bioorg Med Chem Lett. 2003 Feb 10;13(3):347-50.Imidazopyrimidines, potent inhibitors of p38 MAP kinase.
Ref 526668J Med Chem. 2003 Jul 17;46(15):3230-44.Novel substituted pyridinyl imidazoles as potent anticytokine agents with low activity against hepatic cytochrome P450 enzymes.
Ref 552972Successful structure-based design of recent p38 MAP kinase inhibitors. Curr Top Med Chem. 2009;9(7):655-76.
Ref 526904J Med Chem. 2003 Dec 18;46(26):5651-62.Synthesis and structure-activity relationship of aminobenzophenones. A novel class of p38 MAP kinase inhibitors with high antiinflammatory activity.

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