Doramapimod (BIRB 796)

製品コードS1574 バッチS157406

印刷

化学情報

Chemical Structure Synonyms N/A Storage
(From the date of receipt)		 3 years -20°C powder
1 years -80°C in solvent
化学式

C31H37N5O3
分子量 527.66 CAS No. 285983-48-4
Solubility (25°C)* 体外 DMSO 100 mg/mL (189.51 mM)
Ethanol 100 mg/mL (189.51 mM)
Water Insoluble
体内 （毎回新しく調製した物を用意してください）
Homogeneous suspension
CMC-NA
≥5mg/ml Taking the 1 mL working solution as an example, add 5 mg of this product to 1 ml of CMC-Na solution, mix evenly to obtain a homogeneous suspension with a final concentration of 5 mg/ml.
Clear solution
5%DMSO 40%PEG300 5%Tween80 50%ddH2O

この製剤はselleckのラボで検証済みです。上記の溶解方法がご要望を満たさない場合、selleckの営業担当までお問い合わせ頂ければ、個別の試験を行います。

 5.000mg/ml (9.48mM) Taking the 1 mL working solution as an example, add 50 μL of 100 mg/ml clarified DMSO stock solution to 400 μL of PEG300, mix evenly to clarify it; add 50 μL of Tween80 to the above system, mix evenly to make it clear; then continue to add 500 μL of ddH2O to adjust the volume to 1 mL. The mixed solution should be used immediately for optimal results. 
* <1 mg/ml means slightly soluble or insoluble.
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.

溶剤液（一定の濃度）を調合する

生物活性

製品説明 Doramapimod (BIRB 796) は、細胞を含まないアッセイでp38α/β/γ/δに対して38 nM、65 nM、200 nM、520 nMのIC50を持つpan-p38 MAPK阻害剤であり、THP-1細胞では0.1 nMのKdでp38αに結合し、JNK2と比較して330倍高い選択性を示します。c-RAF、Fyn、Lckに対しては弱い阻害作用を示し、ERK-1、SYK、IKK2に対しては有意な阻害作用を示しません。
in vitro

Doramapimod (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. This compound greatly improves binding affinity by forming a hydrogen bond between the morpholine oxygen and the ATP-binding domain of p38α. It represents one of the most potent and slowest dissociating inhibitors against human p38 MAP kinase now known.

It 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. It blocks the stress-induced phosphorylation of the scaffold protein SAP97, which is a physiological substrate of SAPK3/p38γ. This compound 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.

It blocks baseline and upregulation of p38 MAPK and Hsp27 phosphorylation, thereby enhancing cytotoxicity and caspase activation. This compound downregulates IL-6 and VEGF secretion in BMSCs triggered by TNF-α and TGF-β1.

It 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. This compound also inhibits B-Raf and Abl with IC50 of 83 nM and 14.6 μM, respectively.

in vivo

Doramapimod (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.

This compound has good pharmacokinetic performance even after oral administration in mice.

特徴 The first p38 MAPK inhibitor to be tested in a phase III clinical trial.

プロトコル(参考用のみ)

キナーゼアッセイ 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 Doramapimod (BIRB 796) for 30 min. The 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. This compound is analyzed in each experiment and the 95% confidence intervals for the EC50 are between 16 and 22 nM.
細胞アッセイ 細胞株 Cell-free assays
濃度
反応時間
実験の流れ
動物実験 動物モデル Collagen-induced arthritis in female Balb/c mice
投薬量 1 mg/kg (intravenous) or 10 mg/kg (oral)
投与方法 Intravenous injection or by oral

参考

  • https://pubmed.ncbi.nlm.nih.gov/11896401/
  • https://pubmed.ncbi.nlm.nih.gov/12086485/
  • https://pubmed.ncbi.nlm.nih.gov/15755732/
  • https://pubmed.ncbi.nlm.nih.gov/17173546/
  • https://pubmed.ncbi.nlm.nih.gov/20621496/
  • https://pubmed.ncbi.nlm.nih.gov/14561087/

カスタマーフィードバック

Data from [Data independently produced by Int J Cancer, 2014, 134(3), 575-86]

Data from [Data independently produced by Biochem J, 2014, 449(2), 497-506]

Data from [Data independently produced by Blood, 2012, 119(26), 6255-8]

Selleckの高級品が、幾つかの出版された研究調査結果（以下を含む）で使われた：

First-in-class ultralong-target-residence-time p38α inhibitors as a mitosis-targeted therapy for colorectal cancer [ Nat Cancer, 2025, 6(2):259-277] PubMed: 39820127
p38 mediated ACSL4 phosphorylation drives stress-induced esophageal squamous cell carcinoma growth through Src myristoylation [ Nat Commun, 2025, 16(1):3319] PubMed: 40195298
Heparan sulfate regulates myofibroblast heterogeneity and function to mediate niche homeostasis during alveolar morphogenesis [ Nat Commun, 2025, 16(1):1834] PubMed: 39979343
Inhibition of DEK restores hematopoietic stem cell function in Fanconi anemia [ J Exp Med, 2025, 222(3)e20241248] PubMed: 39836085
Drug screening in 3D microtumors reveals DDR1/2-MAPK12-GLI1 as a vulnerability in cancer-associated fibroblasts [ Cell Rep Med, 2025, S2666-3791(25)00430-6] PubMed: 40975064
Tumor cell-released autophagosomes (TRAPs) induce PD-L1-decorated NETs that suppress T-cell function to promote breast cancer pulmonary metastasis [ J Immunother Cancer, 2024, 12(6)e009082] PubMed: 38926151
Vitamin D3 inhibits p38 MAPK and senescence-associated inflammatory mediator secretion by senescent fibroblasts that impacts immune responses during ageing [ Aging Cell, 2024, e14093.] PubMed: 38287646
Lack of p38 activation in T cells increases IL-35 and protects against obesity by promoting thermogenesis [ EMBO Rep, 2024, 10.1038/s44319-024-00149-y] PubMed: 38730210
Cetylpyridinium chloride triggers paraptosis to suppress pancreatic tumor growth via the ERN1-MAP3K5-p38 pathway [ iScience, 2024, 27(8):110598] PubMed: 39211547
Reporter cell lines to screen for inhibitors or regulators of the KRAS-RAF-MEK1/2-ERK1/2 pathway [ Biochem J, 2024, 481(6):405-422] PubMed: 38381045

長期の保管のために-20°Cの下で製品を保ってください。

人間や獣医の診断であるか治療的な使用のためにでない。

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