Doramapimod (BIRB 796)

製品コードS1574 バッチS157404

化学情報

	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
* <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) 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 K_d 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.
in vitro	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]
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. ^[1] BIRB 796 has good pharmacokinetic performance even after oral administration in mice. ^[2]
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
キナーゼアッセイ	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.
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

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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：

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
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
Skeletal muscle-secreted DLPC orchestrates systemic energy homeostasis by enhancing adipose browning [ Nat Commun, 2023, 14(1):7916]	PubMed: 38036537
Chemical-induced epigenome resetting for regeneration program activation in human cells [ Cell Rep, 2023, 42(6):112547]	PubMed: 37224020
Role of the p38/AKT Pathway in the Promotion of Cell Proliferation by Serum Heat Inactivation [ Int J Mol Sci, 2023, 10.3390/ijms242216538]	PubMed: 38003726
USP24-dependent stabilization of Runx2 recruits a p300/NCOA3 complex to transactivate ADAMTS genes and promote degeneration of intervertebral disc in chronic inflammation mice [ Biol Direct, 2023, 18(1):37]	PubMed: 37415159
Cellular stress induces non-canonical activation of the receptor tyrosine kinase EphA2 through the p38-MK2-RSK signaling pathway [ J Biol Chem, 2023, S0021-9258(23)00341-1]	PubMed: 37059179
Actin cytoskeleton remodeling disrupts physical barriers to infection and presents entry receptors to respiratory syncytial virus [ J Gen Virol, 2023, 104(11)001923]	PubMed: 38015055
2-Methoxyestradiol inhibits the proliferation level in keloid fibroblasts through p38 in the MAPK/Erk signaling pathway [ J Cosmet Dermatol, 2023, 10.1111/jocd.15810]	PubMed: 37190848
Precision Combination Therapies Based on Recurrent Oncogenic Coalterations [ Cancer Discov, 2022, 12(6):1542-1559]	PubMed: 35412613

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。

各々の製品のための特定の保管と取扱い情報は、製品データシートの上で示されます。大部分のSelleck製品は、推薦された状況の下で安定です。製品は、推薦された保管温度と異なる温度で、時々出荷されます。長期の保管のために必要とされてそれと異なる温度で、多くの製品は、短期もので安定です。品質を維持するが、夜通しの積荷のために最も経済的な貯蔵状況を用いてあなたの送料を保存する状況の下に、製品が出荷されることを、我々は確実とします。製品の受領と同時に、製品データシートの上で貯蔵推薦に従ってください。