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Doramapimod (BIRB 796) p38 MAPK Inhibiteur

Name: Doramapimod (BIRB 796)
Brand: Selleck Chemicals
SKU: S1574
Rating: 5 (130 reviews)

Réf. Catalogue: S1574

Doramapimod (BIRB 796) est un inhibiteur pan-p38 MAPK avec des IC50 de 38 nM, 65 nM, 200 nM et 520 nM pour p38α/β/γ/δ dans des essais acellulaires. Il se lie à p38α avec un K_d de 0,1 nM dans les cellules THP-1, montrant une sélectivité 330 fois supérieure par rapport à JNK2, une faible inhibition pour c-RAF, Fyn et Lck, et une inhibition insignifiante de ERK-1, SYK, IKK2.

Doramapimod (BIRB 796) p38 MAPK Inhibiteur Chemical Structure

Structure chimique

Poids moléculaire: 527.66

Aller à

Contrôle Qualité (Quality Control)

Lot : Pureté : 99.99%

99.99

Cibles apparentées	ERK Raf JNK MEK Ras KRas S6 Kinase MAP4K TAK1 Mixed Lineage Kinase
Autre p38 MAPK Inhibiteurs	SB202190 SB203580 (Adezmapimod) PH-797804 Ralimetinib (LY2228820) dimesylate VX-702 Losmapimod SB239063 Asiatic Acid Neflamapimod (VX-745) BMS-582949

Culture cellulaire, traitement et concentration de travail
(Cell Culture, Treatment & Working Concentration)

Lignées cellulaires	Type d'essai	Temps d'incubation	Description de l'activité	PMID
HOP-92	Growth Inhibition Assay		IC50=24.3838 μM	SANGER
NCI-H2228	Growth Inhibition Assay		IC50=23.6668 μM	SANGER
CAPAN-1	Growth Inhibition Assay		IC50=22.1884 μM	SANGER
SK-MEL-1	Growth Inhibition Assay		IC50=20.3683 μM	SANGER
DB	Growth Inhibition Assay		IC50=18.7923 μM	SANGER
AN3-CA	Growth Inhibition Assay		IC50=18.1 μM	SANGER
EW-13	Growth Inhibition Assay		IC50=17.9516 μM	SANGER
LC-2-ad	Growth Inhibition Assay		IC50=17.4366 μM	SANGER
ES8	Growth Inhibition Assay		IC50=17.167 μM	SANGER
NCI-H1581	Growth Inhibition Assay		IC50=17.0447 μM	SANGER
HMV-II	Growth Inhibition Assay		IC50=14.2309 μM	SANGER
BEN	Growth Inhibition Assay		IC50=13.1264 μM	SANGER
NBsusSR	Growth Inhibition Assay		IC50=10.8235 μM	SANGER
MS-1	Growth Inhibition Assay		IC50=10.8235 μM	SANGER
BFTC-905	Growth Inhibition Assay		IC50=10.1233 μM	SANGER
NCI-SNU-1	Growth Inhibition Assay		IC50=9.06739 μM	SANGER
MPP-89	Growth Inhibition Assay		IC50=8.46251 μM	SANGER
T-24	Growth Inhibition Assay		IC50=8.40673 μM	SANGER
KP-N-YN	Growth Inhibition Assay		IC50=8.2019 μM	SANGER
IST-MES1	Growth Inhibition Assay		IC50=7.95637 μM	SANGER
NCI-H358	Growth Inhibition Assay		IC50=7.538 μM	SANGER
GOTO	Growth Inhibition Assay		IC50=6.39161 μM	SANGER
DU-145	Growth Inhibition Assay		IC50=3.93811 μM	SANGER
EoL-1-cell	Growth Inhibition Assay		IC50=0.34763 μM	SANGER
KYSE-270	Growth Inhibition Assay		IC50=24.5573 μM	SANGER
HCC1806	Growth Inhibition Assay		IC50=24.7799 μM	SANGER
HuO-3N1	Growth Inhibition Assay		IC50=25.8185 μM	SANGER
HOS	Growth Inhibition Assay		IC50=25.9292 μM	SANGER
KYSE-510	Growth Inhibition Assay		IC50=26.1612 μM	SANGER
COLO-741	Growth Inhibition Assay		IC50=26.3329 μM	SANGER
H-EMC-SS	Growth Inhibition Assay		IC50=26.9245 μM	SANGER
HCC1937	Growth Inhibition Assay		IC50=27.2238 μM	SANGER
NCI-H2126	Growth Inhibition Assay		IC50=27.3975 μM	SANGER
NCI-H1703	Growth Inhibition Assay		IC50=28.0413 μM	SANGER
U-2-OS	Growth Inhibition Assay		IC50=28.5515 μM	SANGER
DBTRG-05MG	Growth Inhibition Assay		IC50=28.5651 μM	SANGER
MHH-ES-1	Growth Inhibition Assay		IC50=31.941 μM	SANGER
HCC1419	Growth Inhibition Assay		IC50=32.1119 μM	SANGER
HOP-62	Growth Inhibition Assay		IC50=32.2701 μM	SANGER
AM-38	Growth Inhibition Assay		IC50=32.9931 μM	SANGER
NCI-H2009	Growth Inhibition Assay		IC50=33.4007 μM	SANGER
EM-2	Growth Inhibition Assay		IC50=33.5511 μM	SANGER
SW1116	Growth Inhibition Assay		IC50=34.4838 μM	SANGER
SK-N-AS	Growth Inhibition Assay		IC50=35.0714 μM	SANGER
ChaGo-K-1	Growth Inhibition Assay		IC50=35.6032 μM	SANGER
RT-112	Growth Inhibition Assay		IC50=35.9879 μM	SANGER
HTC-C3	Growth Inhibition Assay		IC50=36.2355 μM	SANGER
SK-NEP-1	Growth Inhibition Assay		IC50=36.6106 μM	SANGER
LB831-BLC	Growth Inhibition Assay		IC50=37.6541 μM	SANGER
CTB-1	Growth Inhibition Assay		IC50=38.4512 μM	SANGER
MOLT-4	Growth Inhibition Assay		IC50=38.8391 μM	SANGER
SW756	Growth Inhibition Assay		IC50=40.9385 μM	SANGER
CAL-72	Growth Inhibition Assay		IC50=42.03 μM	SANGER
KNS-62	Growth Inhibition Assay		IC50=42.6296 μM	SANGER
KARPAS-299	Growth Inhibition Assay		IC50=43.3233 μM	SANGER
HEL	Growth Inhibition Assay		IC50=45.4646 μM	SANGER
KP-4	Growth Inhibition Assay		IC50=46.7361 μM	SANGER
NEC8	Growth Inhibition Assay		IC50=47.1661 μM	SANGER
G-402	Growth Inhibition Assay		IC50=48.7012 μM	SANGER
Sf21	Function assay		Binding affinity to wild type human biotin labelled p38 alpha (9 to 352 residues) expressed in sf21 insect cells SPR analysis, Kd = 0.000123 μM.	28834431
THP1	Function assay		Inhibition of LPS-induced TNFalpha production in human THP1 cells, IC50 = 0.013 μM.	18325768
U937	Antiinflammatory assay	2 hrs	Antiinflammatory activity in differentiated human U937 cells assessed as inhibition of LPS-induced TNFalpha production preincubated for 2 hrs followed by LPS-stimulation for 4 hrs by sandwich ELISA relative to vehicle-treated control, IC50 = 0.015 μM.	26800309
THP1	Function assay		Inhibition of LPS-induced TNFalpha production in human THP1 cells, IC50 = 0.018 μM.	19356929
THP1	Function assay		Inhibition of LPS-induced tumor necrosis factor-alpha (TNF-alpha) production in THP-1 cells, EC50 = 0.018 μM.	12086485
THP	Function assay		Tested for inhibition of Tumor necrosis factor, alpha in THP cells, EC50 = 0.018 μM.	14561087
THP1	Function assay		Inhibition of LPS-induced TNFalpha production in THP1 cells, IC50 = 0.018 μM.	17560108
THP1	Function assay		Inhibition of LPS-stimulated TNFalpha production in human THP1 cells, IC50 = 0.018 μM.	18462940
HLF	Function assay		Inhibition of p38alpha phosphorylation in IL-1-alpha-stimulated HLF cells, IC50 = 0.047 μM.	18602262
HLF	Function assay		Inhibition of HSP27 phosphorylation in IL-1-alpha-stimulated HLF cells, IC50 = 0.058 μM.	18602262
HEK293F	Function assay		Inhibition of sodium arsenate activated N-terminal GST-tagged Brugia malayi MPK1 expressed in HEK293F cells using FAM-p38tide as substrate by IMAP assay, IC50 = 0.14 μM.	29541362
BL21(DE3)	Function assay		Inhibition of p38alpha active form expressed in Escherichia coli BL21(DE3) cells by HTRF assay, IC50 = 0.25 μM.	19928858
whole blood cells	Antiinflammatory assay	4 hrs	Antiinflammatory activity in human whole blood cells assessed as inhibition of LPS-induced TNFalpha production after 4 hrs by time-resolved fluorescence assay, IC50 = 0.6 μM.	22749282
A673	qHTS assay		qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for A673 cells	29435139
DAOY	qHTS assay		qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for DAOY cells	29435139
RD	qHTS assay		qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for RD cells	29435139
SK-N-SH	qHTS assay		qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for SK-N-SH cells	29435139
MG 63 (6-TG R)	qHTS assay		qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for MG 63 (6-TG R) cells	29435139
NB1643	qHTS assay		qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for NB1643 cells	29435139
SK-N-MC	qHTS assay		qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for SK-N-MC cells	29435139
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Informations chimiques, stockage et stabilité (Chemical Information, Storage & Stability)

Poids moléculaire	527.66	Formule	C₃₁H₃₇N₅O₃	Stockage (À compter de la date de réception)	3 ans-20°Cpoudre
N° CAS	285983-48-4	Télécharger le SDF		Stockage des solutions mères	1 an-80°Cen solvant 1 mois-20°Cen solvant
Synonymes	N/A			Smiles	CC1=CC=C(C=C1)N2C(=CC(=N2)C(C)(C)C)NC(=O)NC3=CC=C(C4=CC=CC=C43)OCCN5CCOCC5

Solubilité (Solubility)

In vitro
Lot:

DMSO : 100 mg/mL (189.51 mM)
(Le DMSO contaminé par l'humidité peut réduire la solubilité. Utiliser du DMSO frais et anhydre.)

Ethanol : 100 mg/mL

Water : Insoluble

Calculateur de molarité

Masse	Concentration	Volume	Poids moléculaire
=	×	×

Calculateur de dilution Calculateur de poids moléculaire

In vivo Lot:
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 1 40%PEG300 2 5%Tween80 3 50%ddH2O Validé par les laboratoires Selleck. Si vous avez besoin d'ajustements à cette formulation, contactez notre équipe commerciale pour des tests personnalisés.	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.
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.
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.
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.
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.

Calculateur de formulation in vivo (Solution claire)

Étape 1 : Saisir les informations ci-dessous (Recommandé : Un animal supplémentaire pour tenir compte des pertes pendant l'expérience)

Dosage : mg/kg Poids moyen des animaux : g Volume de dosage par animal :μL Nombre d'animaux :

Étape 2 : Saisir la formulation in vivo (Ceci est seulement le calculateur, pas la formulation. Veuillez nous contacter d'abord s'il n'y a pas de formulation in vivo dans la section Solubilité.)

% DMSO + % + % Tween 80 + % ddH₂O

%DMSO+ %

Résultats du calcul :

Concentration de travail : mg/ml;

Méthode de préparation du liquide maître DMSO : mg médicament prédissous dans μL DMSO ( Concentration du liquide maître mg/mL, Veuillez nous contacter d'abord si la concentration dépasse la solubilité du DMSO du lot de médicament. )

Méthode de préparation de la formulation in vivo : Prendre μL DMSO liquide maître, puis ajouterμL PEG300, mélanger et clarifier, puis ajouterμL Tween 80, mélanger et clarifier, puis ajouter μL ddH₂O, mélanger et clarifier.

Méthode de préparation de la formulation in vivo : Prendre μL DMSO liquide maître, puis ajouter μL Huile de maïs, mélanger et clarifier.

Note : 1. Veuillez vous assurer que le liquide est clair avant d'ajouter le solvant suivant.
2. Assurez-vous d'ajouter le(s) solvant(s) dans l'ordre. Vous devez vous assurer que la solution obtenue, lors de l'ajout précédent, est une solution claire avant de procéder à l'ajout du solvant suivant. Des méthodes physiques telles que le vortex, les ultrasons ou le bain-marie chaud peuvent être utilisées pour faciliter la dissolution.

Mécanisme d'action (Mechanism of Action)

Caractéristiques	The first p38 MAPK inhibitor to be tested in a phase III clinical trial.
Targets/IC₅₀/Ki	JNK2 c-RAF Fyn p38α (Cell-free assay) 0.1 nM(Kd) p38α 38 nM
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.
Essai kinase	Procédures pour le dosage cellulaire sur THP-1 de l'inhibition de la production de TNF-α stimulée par le LPS
Essai kinase	Les cellules THP-1 sont préincubées en présence et en l'absence de Doramapimod (BIRB 796) pendant 30 min. Le mélange cellulaire est stimulé avec du LPS (1 μg/mL final) et l'incubation est poursuivie pendant la nuit (18-24 heures) comme ci-dessus. Le surnageant est analysé pour le TNF-α humain par un ELISA disponible dans le commerce. Les données sont combinées et analysées par régression non linéaire utilisant un modèle logistique à trois paramètres pour obtenir une valeur EC50. Ce composé est analysé dans chaque expérience et les intervalles de confiance à 95 % pour l'EC50 se situent entre 16 et 22 nM.
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.
Références	[1] https://pubmed.ncbi.nlm.nih.gov/11896401/ [2] https://pubmed.ncbi.nlm.nih.gov/12086485/ [3] https://pubmed.ncbi.nlm.nih.gov/15755732/ [4] https://pubmed.ncbi.nlm.nih.gov/17173546/ [5] https://pubmed.ncbi.nlm.nih.gov/20621496/ [6] https://pubmed.ncbi.nlm.nih.gov/14561087/

Applications (Applications)

Méthodes	Biomarqueurs	Images	PMID
Western blot	p-p38 / γ-H2AX mTOR / p-S6K / S6K / p-MK2 / MK2 / p-Hsp27 / Hsp27 p-p38 / p38		27082306

Informations sur l'essai clinique (Clinical Trial Information)

(données du https://clinicaltrials.gov, mis à jour le 2024-05-22)

Numéro NCT	Recrutement	Conditions	Promoteur/Collaborateurs	Date de début	Phases
NCT02211885	Completed	Healthy	Boehringer Ingelheim	October 2002	Phase 1

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