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Doramapimod (BIRB 796) p38 MAPK Remmer

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

Cat.nr.: S1574

Doramapimod (BIRB 796) is een pan-p38 MAPK-remmer met IC50 van 38 nM, 65 nM, 200 nM en 520 nM voor p38α/β/γ/δ in celvrije assays. Het bindt p38α met K_d van 0,1 nM in THP-1 cellen, met 330-voudig hogere selectiviteit versus JNK2, zwakke remming voor c-RAF, Fyn en Lck, en onbeduidende remming van ERK-1, SYK, IKK2.

Doramapimod (BIRB 796) p38 MAPK Remmer Chemical Structure

Chemische structuur

Molecuulgewicht: 527.66

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Kwaliteitscontrole (Quality Control)

Batch: Zuiverheid: 99.99%

99.99

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

Celkweek, behandeling & werkzame concentratie
(Cell Culture, Treatment & Working Concentration)

Cellijnen	Assaytype	Incubatietijd	Activiteitsbeschrijving	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
Klik om meer experimentele gegevens over cellijnen te bekijken

Chemische informatie, opslag en stabiliteit (Chemical Information, Storage & Stability)

Molecuulgewicht	527.66	Formule	C₃₁H₃₇N₅O₃	Opslag (vanaf de datum van ontvangst)	3 jaar-20°Cpoeder
CAS-nr.	285983-48-4	SDF downloaden		Opslag van stamoplossingen	1 jaar-80°Cin oplosmiddel 1 maand-20°Cin oplosmiddel
Synoniemen	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

Oplosbaarheid (Solubility)

In vitro
Batch:

DMSO : 100 mg/mL (189.51 mM)
(Met vocht verontreinigd DMSO kan de oplosbaarheid verminderen. Gebruik verse, watervrije DMSO.)

Ethanol : 100 mg/mL

Water : Insoluble

Molariteitscalculator

Massa	Concentratie	Volume	Molecuulgewicht
=	×	×

Verdunningscalculator Molecuulgewichtcalculator

In vivo Batch:
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 Gevalideerd door Selleck labs. Mocht u aanpassingen aan deze formulering nodig hebben, neem dan contact op met ons verkoopteam voor aangepaste tests.	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.

In vivo formulatiecalculator (heldere oplossing)

Stap 1: Voer onderstaande informatie in (Aanbevolen: een extra dier om rekening te houden met verlies tijdens het experiment)

Dosering: mg/kg Gemiddeld gewicht van dieren: g Doseervolume per dier:μL Aantal dieren:

Stap 2: Voer de in vivo formulering in (Dit is alleen de calculator, geen formulering. Neem eerst contact met ons op als er geen in vivo formulering is in de sectie oplosbaarheid.)

% DMSO + % + % Tween 80 + % ddH₂O

%DMSO+ %

Berekeningsresultaten:

Werkconcentratie: mg/ml;

Methode voor het bereiden van DMSO-moedervloeistof: mg geneesmiddel vooropgelost in μL DMSO ( Concentratie moedervloeistof mg/mL, Neem eerst contact met ons op als de concentratie de DMSO-oplosbaarheid van de batch van het geneesmiddel overschrijdt. )

Methode voor het bereiden van in vivo formulering: Neem μL DMSO moedervloeistof, voeg daarna toeμL PEG300, mengen en verhelderen, daarna toevoegenμL Tween 80, mengen en verhelderen, daarna toevoegen μL ddH₂O, mengen en verhelderen.

Methode voor het bereiden van in vivo formulering: Neem μL DMSO moedervloeistof, voeg daarna toe μL Maïsolie, mengen en verhelderen.

Opmerking: 1. Zorg ervoor dat de vloeistof helder is voordat u het volgende oplosmiddel toevoegt.
2. Zorg ervoor dat u het/de oplosmiddel(en) in de juiste volgorde toevoegt. U moet ervoor zorgen dat de verkregen oplossing, bij de vorige toevoeging, een heldere oplossing is voordat u verdergaat met het toevoegen van het volgende oplosmiddel. Fysieke methoden zoals vortexen, ultrasoon of een warmwaterbad kunnen worden gebruikt om het oplossen te bevorderen.

Werkingsmechanisme (Mechanism of Action)

Kenmerken	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.
Kinase Assay	Procedures voor de THP-1 cellulaire assay voor remming van LPS-gestimuleerde TNF-α productie
Kinase Assay	THP-1 cellen worden 30 min voorgeïncubeerd in de aanwezigheid en afwezigheid van Doramapimod (BIRB 796). Het celmengsel wordt gestimuleerd met LPS (1 μg/mL eindconcentratie) en de incubatie wordt 's nachts (18-24 uur) voortgezet zoals hierboven beschreven. Het supernatant wordt geanalyseerd op humaan TNF-α met een commercieel verkrijgbare ELISA. Gegevens worden gecombineerd en geanalyseerd door middel van niet-lineaire regressie met gebruik van een logistisch model met drie parameters om een EC50-waarde te verkrijgen. Deze verbinding wordt in elk experiment geanalyseerd en de 95%-betrouwbaarheidsintervallen voor de EC50 liggen tussen 16 en 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.
Referenties	[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/

Toepassingen (Applications)

Methoden	Biomarkers	Afbeeldingen	PMID
Western blot	p-p38 / γ-H2AX mTOR / p-S6K / S6K / p-MK2 / MK2 / p-Hsp27 / Hsp27 p-p38 / p38		27082306

Informatie over klinische proeven (Clinical Trial Information)

(gegevens van https://clinicaltrials.gov, bijgewerkt op 2024-05-22)

NCT-nummer	Werving	Aandoeningen	Sponsor/medewerkers	Startdatum	Fasen
NCT02211885	Completed	Healthy	Boehringer Ingelheim	October 2002	Phase 1

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