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Research Area
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Description
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Inflammation |
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Biological Activity
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Description
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BIRB 796 (Doramapimod) is a highly selective p38α MAPK inhibitor to TNF-α with EC50 of 18 nM. |
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Targets
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TNF-α |
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IC50 |
18 nM (EC50) [1] |
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In Vitro
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BIRB 796 shows no significant inhibition to ERK-1, SYK, IKK2β, ZAP-70, EGF receptor kinase, HER2, protein kinase A (PKA), PKC, PKC-α, PKC-β (I and II) and PKC-γ. BIRB 796 greatly improves binding affinity by forming a hydrogen bond between the morpholine oxygen and the ATP-binding domain of p38α. BIRB 796 represents one of the most potent and slowest dissociating inhibitors against human p38 MAP kinase now known. [1] BIRB 796 potently inhibits c-Raf-1 and Jnk2α2 with IC50 of 1.4 and 0.1 nM, respectively. [2] BIRB796 also inhibits the activity and the activation of SAPK3/p38γ at a higher concentration than it does in p38α. BIRB796 blocks the stress-induced phosphorylation of the scaffold protein SAP97, which is a physiological substrate of SAPK3/p38γ. BIRB796 blocks JNK1/2 activation and activity in HEK293 cells, while not inhibits the activation and activity of ERK1/ERK2 in Hela cells. Moreover, the binding of BIRB796 to the p38 MAPKs or JNK1/2 is impairing their phosphorylation by the upstream kinase MKK6 or MKK4 rather than enhancing their dephosphorylation. [3] BIRB 796 blocks baseline and bortezomib-triggered upregulation of p38 MAPK and Hsp27 phosphorylation, thereby enhancing cytotoxicity and caspase activation. BIRB 796 downregulates IL-6 and VEGF secretion in BMSCs triggered by TNF-α and TGF-β1. [4] BIRB-796 has a pyrazole scaffold that places a lipophilic t-butyl group into the lower selectivity site and a tolyl ring into the upper selectivity site. BIRB-796 also inhibits B-Raf and Abl with IC50 of 83?nM and 14.6?μM, respectively. [5] |
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In Vivo
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BIRB 796 (30 mg/kg) inhibits 84% of TNF-α in LPS-stimulated mice and demonstrates efficacy in a mouse model of established collagen-induced arthritis. [1] BIRB 796 has good pharmacokinetic performance even after oral administration in mice. [2] |
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Clinical Trials
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Boehringer Ingelheim has announced the discontinuation of BIRB 796 R&D project in 2005. |
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Features
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BIRB 796 is the first p38 MAPK inhibitor to reach phase III clinical trial. |
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Protocol
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Kinase Assay
[6]
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| Procedures for the THP-1 cellular assay for inhibition of LPS-stimulated TNF-α production |
THP-1 cells are preincubated in the presence and absence of BIRB 796 for 30 min. Cell mixture is stimulated with LPS (1 μg/mL final) and incubation continued overnight (18?24 hours) as above. Supernatant is analyzed for human TNF-α by a commercially available ELISA. Data are combined and analyzed by nonlinear regression using a three parameter logistic model to obtain an EC50 value. BIRB 796 is analyzed in each experiment and the 95% confidence intervals for the EC50 are between 16 and 22 nM. |
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Animal Study
[2]
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| Animal Models |
Collagen-induced arthritis in female Balb/c mice |
| Formulation |
70% PEG400 (intravenous) or 100% PEG400 (oral) |
| Doses |
1 mg/kg (intravenous) or 10 mg/kg (oral) |
| Administration |
Intravenous injection or by oral |
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References |
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[1] Pargellis C, et al. Nat Struct Biol, 2002, 9(4), 268-272.
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[2] Regan J, et al. J Med Chem, 2002, 45(14), 2994-3008.
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[3] Kuma Y, et al. J Biol Chem, 2005, 280(20), 19472-19479.
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[4] Yasui H, et al. Br J Haematol, 2007, 136(3), 414-423.
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[5] Dietrich J, et al. Bioorg Med Chem. 2010, 18(15), 5738-5748.
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[6] Regan J, et al. J Med Chem, 2003, 46(22), 4676-4686.
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