Doramapimod (BIRB 796)
Molecular Weight(MW): 527.66
Doramapimod (BIRB 796) is a 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.
Cited by 17 Publications
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Lympho-myeloid potential assessed by FACS analysis of human CD19 (B-lymphoid cells) and CD33/CD15 (myeloid cells) in bone marrow of NSG recipient mice, 17 weeks after transplantation. Each plot represents an animal from the experiment presented in panel.
Blood 2012 119(26), 6255-8. Doramapimod (BIRB 796) purchased from Selleck.
A p38α/ERK crosstalk exists in CRC cells and tissues. Use of a structurally and functionally different p38α inhibitor (BIRB-796) confirms ERK1/2 phospho-activation. Using BIRB-796 for up to 72 h triggers MEK-ERK1/2 signaling in HT-29 cells.
Cancer Lett 2012 324(1), 98-108. Doramapimod (BIRB 796) purchased from Selleck.
Effect of blockade of p38 or MEK on MK2 activation following TLR stimulation in moDC. MoDC were pre-treated with p38 inhibitors SB203580 10 mM (S), BIRB0796 (B) 0.1 or 1.0 mM or MEK inhibitor UO126 10 mM (U) for 1hr followed by poly I:C/R848 stimulation for 30 min then Western blotted for p-MK2 with β-actin loading control.
Int J Cancer 2014 134(3), 575-86. Doramapimod (BIRB 796) purchased from Selleck.
Inhibition of p38 MAPK activity prevents induction of autophagy by glucose. NIH 3T3 cells were incubated in KH medium without glucose in the presence of the p38 MAPK inhibitor BIRB796 (50 nM, middle panels). After 30 min, glucose (10 mM) and lysosomal inhibitors were added to the indicated samples and cells were further incubated for 2 h. Cell lysates were collected and processed for SDS/PAGE. LC3 levels were detected and actin served as a loading control. The values shown in the histograms represent means盨.D. from three independent experiments with the LC3-II levels normalized to actin and expressed as a percentage of the values of KH medium without glucose. *P<0.05. Glc, glucose; w/o, without.
Biochem J 2014 449(2), 497-506. Doramapimod (BIRB 796) purchased from Selleck.
Purity & Quality Control
Choose Selective p38 MAPK Inhibitors
|Description||Doramapimod (BIRB 796) is a 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.|
|Features||The first p38 MAPK inhibitor to be tested in a phase III clinical trial.|
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. 
|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. |
-  Pargellis C, et al. Nat Struct Biol, 2002, 9(4), 268-272.
-  Regan J, et al. J Med Chem, 2002, 45(14), 2994-3008.
-  Kuma Y, et al. J Biol Chem, 2005, 280(20), 19472-19479.
|In vitro||DMSO||106 mg/mL (200.88 mM)|
|Ethanol||106 mg/mL (200.88 mM)|
|In vivo||30% PEG400+0.5% Tween80+5% propylene glycol||30 mg/mL|
* 1 mg/ml means slightly soluble or insoluble.
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Clinical Trial Information
|NCT Number||Recruitment||Conditions||Sponsor/Collaborators||Start Date||Phases|
|NCT02214888||Terminated||Arthritis, Rheumatoid||Boehringer Ingelheim||May 2003||Phase 2|
|NCT02211885||Completed||Healthy||Boehringer Ingelheim||October 2002||Phase 1|
|NCT02209753||Completed||Psoriasis||Boehringer Ingelheim||June 2001||Phase 2|
|NCT02209805||Completed||Healthy||Boehringer Ingelheim||January 2001||Phase 1|
Answers to questions you may have can be found in the inhibitor handling instructions. Topics include how to prepare stock solutions, how to store inhibitors, and issues that need special attention for cell-based assays and animal experiments.
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