product name BIRB 796 (Doramapimod)
Description: BIRB 796, also known as doramapimod, is a highly potent pan-p38 MAPK inhibitor with IC50 of 38 nM, 65 nM, 200 nM and 520 nM for p38α/β/γ/δ in cell-free assays, and binds p38α with Kd of 0.1 nM in THP-1 cells, 330-fold greater selectivity versus JNK2, weak inhibition for c-RAF, Fyn and Lck, insignificant inhibition of ERK-1, SYK, IKK2. BIRB-796 is a member of the N-pyrazole-N-naphthly urea class of p38MAPK inhibitors which binds to the kinase with both slow association and dissociation rates. BIRB -796 has entered clinical trials for the treatment of autoimmune diseases.
References: Nat Struct Biol. 2002 Apr;9(4):268-72; J Med Chem. 2002 Jul 4;45(14):2994-3008.
527.66
Formula
C31H37N5O3
CAS No.
285983-48-4
Storage
-20℃ for 3 years in powder form
-80℃ for 2 years in solvent
Solubility (In vitro)
DMSO: 106 mg/mL (200.9 mM)
Water: <1 mg/mL
Ethanol: 106 mg/mL (200.9 mM)
Solubility (In vivo)
30% PEG400+0.5% Tween80+5% Propylene glycol: 30 mg/mL
Synonyms
other peoduct :
| In Vitro |
In vitro activity: 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. BIRB 796 potently inhibits c-Raf-1 and Jnk2α2 with IC50 of 1.4 and 0.1 nM, respectively. 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. 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. 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. Kinase Assay: BIRB 796 (Doramapimod) is a highly selective p38α inhibitor of MAPK with Kd of 0.1 nM, 330-fold greater selectivity versus JNK2, weak inhibition for c-RAF, Fyn and Lck, insignificant inhibition of ERK-1, SYK, IKK2, ZAP-70, EGFR, HER2, PKA, PKC, PKCα/β/γ. Cell Assay: BIRB 796 inhibited baseline and Dex-induced phosphorylation of both p38 MAPK and Hsp27 in MM.1S cells. Although MM.1S cell proliferation was strongly inhibited by Dex alone at 24–72 h, BIRB 796 significantly enhanced its growth inhibition. Cell cycle profiling suggests that BIRB 796 augmented Dex-mediated growth inhibition by enhancing apoptosis (Sub-G1 portion: control = 6.1%, BIRB 796 alone = 8.0%, Dex alone = 34.7%, BIRB 796 plus Dex = 45.7%). |
|---|---|
| In Vivo | 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. BIRB 796 has good pharmacokinetic performance even after oral administration in mice. |
| Animal model | Collagen-induced arthritis in female Balb/c mice |
| Formulation & Dosage | Dissolved in 70% PEG400 (intravenous) or 100% PEG400 (oral); 1 mg/kg (intravenous) or 10 mg/kg (oral); i.v. injection or p.o. |
| References | Nat Struct Biol. 2002 Apr;9(4):268-72; J Med Chem. 2002 Jul 4;45(14):2994-3008. |
