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R406 Syk/FLT3 Inhibitor

Name: R406
Brand: Selleck Chemicals
SKU: S2194
Rating: 5 (126 reviews)

Kat.-Nr.: S2194

R406 (R406 besylate) ist ein potenter Syk-Inhibitor mit einer IC50 von 41 nM in zellfreien Assays, der Syk stark, aber nicht Lyn hemmt und eine 5-fach geringere Potenz gegenüber Flt3 aufweist. R406 induziert Apoptose. Phase 1.

Chemische Struktur

Molekulargewicht: 628.63

Springe zu

Qualitätskontrolle (Quality Control)

Charge: Reinheit: 99.43%

99.43

Verwandte Ziele	EGFR VEGFR JAK FGFR PDGFR Src HIF HER2 FLT3 FLT
Weitere Syk Inhibitoren	R406 (free base) PRT062607 (P505-15) HCl Entospletinib (GS-9973) Piceatannol BAY 61-3606 dihydrochloride PRT-060318 2HCl TAK-659 Hydrochloride Lanraplenib (GS-SYK) RO9021 R112

Zellkultur, Behandlung & Arbeitskonzentration
(Cell Culture, Treatment & Working Concentration)

Zelllinien	Assay-Typ	Konzentration	Inkubationszeit	Formulierung	Aktivitätsbeschreibung	PMID
AMO-1	Function Assay	1 μM	3 h		reduces migration	26251761
U266	Function Assay	1 μM	3 h		reduces migration	26251761
Jeko-1	Growth Inhibition Assay		48 h		IC50=5.06826 μM	25835755
Mino	Growth Inhibition Assay		48 h		IC50=5.70854 μM	25835755
Jeko-1	Apoptosis Assay	5 μM	24 h		induces 25.1 ± 3.2 % apoptosis	25835755
primary MCL	Apoptosis Assay	2 µM	24 h		increases significantly apoptosis	25388373
PBMCs	Cell Viability Assay	0-50 μM	24 h	DMSO	inhibits cell viability dose dependently	25127862
PBMCs	Function Assay	5 μM	1 h	DMSO	decreases the cell migration	25127862
CFSE-CD4+ T	Growth Inhibition Assay	0.0625-1 μM	4 d		blocks proliferation of GVHD-derived CD4+ T cells and CD11b+ cells	24679982
CFSE-CD11b+	Growth Inhibition Assay	0.0625-1 μM	8 d		blocks proliferation of GVHD-derived CD4+ T cells and CD11b+ cells	24679982
HMECs	Function Assay	0-10 μM	20 min		inhibits VEGF-stimulated release of NO	24329544
AB5	Apoptosis Assay	0-2.5 μM	48 h	DMSO	induces apoptosis	23398911
JB7	Apoptosis Assay	0-2.5 μM	48 h	DMSO	induces apoptosis	23398911
AB5	Growth Inhibition Assay	0-2.5 μM	48 h	DMSO	induces cell cycle arrest	23398911
JB7	Growth Inhibition Assay	0-2.5 μM	48 h	DMSO	induces cell cycle arrest	23398911
RL	Function Assay	2.5/5 μM	24/48 h	DMSO	induces a potent decrease in MMP-9 mRNA expression	21926965
RL	Function Assay	1/2.5 μM	24 h	DMSO	reduces the activation of Akt and p70S6K	21926965
platelet	Function Assay	1 μm	5 min		inhibits FcγRIIA-mediated platelet aggregation	21848694
platelet	Function Assay	0.05/1/2.5 μM	5 min		inhibits the signaling mechanisms downstream of FcγRIIA	21848694
DoHH2	Apoptosis Assay	0/3/10 μM	48 h		induces cell death significantly	20875408
Jeko-1	Apoptosis Assay	0/3/10 μM	48 h		induces cell death significantly	20875408
Raji	Apoptosis Assay	0/3/10 μM	48 h		induces cell death significantly	20875408
DHL4	Apoptosis Assay	0/1/4 μM	96 h		induces apoptosis dose dependently	18006696
LY7	Apoptosis Assay	0/1/4 μM	96 h		induces apoptosis dose dependently	18006696
LY3	Apoptosis Assay	0/1/4 μM	96 h		induces apoptosis dose dependently	18006696
DHL6	Apoptosis Assay	0/1/4 μM	96 h		induces apoptosis dose dependently	18006696
LY10	Apoptosis Assay	0/1/4 μM	96 h		induces apoptosis dose dependently	18006696
DHL10	Apoptosis Assay	0/1/4 μM	96 h		induces apoptosis dose dependently	18006696
Wsu-NHL	Apoptosis Assay	0/1/4 μM	96 h		induces apoptosis dose dependently	18006696
LY18	Apoptosis Assay	0/1/4 μM	96 h		induces apoptosis dose dependently	18006696
LY1	Apoptosis Assay	0/1/4 μM	96 h		induces apoptosis dose dependently	18006696
DHL8	Apoptosis Assay	0/1/4 μM	96 h		induces apoptosis dose dependently	18006696
DHL4	Apoptosis Assay	4 μM	96 h		induces cleavage of caspases 9 and 3, but not caspase 8	18006696
DHL6	Apoptosis Assay	4 μM	96 h		induces cleavage of caspases 9 and 3, but not caspase 8	18006696
LY3	Apoptosis Assay	4 μM	96 h		induces cleavage of caspases 9 and 3, but not caspase 8	18006696
LY7	Apoptosis Assay	4 μM	96 h		induces cleavage of caspases 9 and 3, but not caspase 8	18006696
DHL4	Function Assay	4 μM	16 h		inhibits tonic BLNK tyrosine phosphorylation	18006696
LY7	Function Assay	4 μM	16 h		inhibits tonic BLNK tyrosine phosphorylation	18006696
LY3	Function Assay	4 μM	16 h		inhibits tonic BLNK tyrosine phosphorylation	18006696
DHL6	Function Assay	4 μM	16 h		inhibits tonic BLNK tyrosine phosphorylation	18006696
LY10	Function Assay	4 μM	16 h		inhibits tonic BLNK tyrosine phosphorylation	18006696
Wsu-NHL	Function Assay	4 μM	16 h		inhibits tonic BLNK tyrosine phosphorylation	18006696
LY18	Function Assay	4 μM	16 h		inhibits tonic BLNK tyrosine phosphorylation	18006696
MV411	Function assay		72 hrs		Inhibition of Flt3 in human MV411 cells assessed as assessed as proliferation after 72 hrs incubation by spectrophotometry, EC50=0.01μM.	24779514
TF1	Function assay		1 hr		Inhibition of Jak2 in erythropoietin-stimulated human TF1 cells assessed as assessed as phospho-Stat5 after 1 hr incubation, EC50=0.013μM.	24779514
neutrophils	Function assay				Inhibition of SYK in human neutrophils cells assessed as reduction in FcepsilonR1/FcgammaR-mediated signaling responses, EC50=0.033μM.	22257213
SK-M-MC	Function assay		1 hr		Inhibition of Ret in human SK-M-MC cells assessed as assessed as phosphorylation after 1 hr incubation, EC50=0.036μM.	24779514
mast cells	Function assay		1 hr		Inhibition of cKit in stem cell factor-stimulated bone marrow derived mouse mast cells assessed as phosphorylation after 1 hr incubation, EC50=0.046μM.	24779514
B-cells	Function assay				Inhibition of SYK in human B-cells cells assessed as reduction in FcepsilonR1/FcgammaR-mediated signaling responses, EC50=0.048μM.	22257213
Ramos	Function assay				Inhibition of Syk in antihuman IgM-stimulated human Ramos cells assessed as decrease in BCR-mediated BLNK phosphorylation by cellular assay, EC50=0.053μM.	24779514
mesangial cells	Function assay				Inhibition of SYK in cultured human mesangial cells assessed as reduction in FcepsilonR1/FcgammaR-mediated signaling responses, EC50=0.056μM.	22257213
SK-N-SH	Function assay				Inhibition of Ret in human SK-N-SH cells, EC50=0.08μM.	22257213
mouse bone marrow cells	Function assay				Inhibition of IL3 dependent proliferation in C57/B16 mouse bone marrow cells using [3H]thymidine by liquid scintillation counting, IC50=0.147μM.	24726806
B-cells	Function assay		1 hr		Inhibition of Syk in alphaIgM-stimulated human B cells assessed as cell proliferation after 1 hr incubation by flow cytometry, EC50=0.151μM.	24779514
THP1	Function assay				Inhibition of SYK in human THP1 cells assessed as reduction in FcepsilonR1/FcgammaR-mediated signaling responses, EC50=0.171μM.	22257213
B-cells	Function assay		1 hr		Inhibition of Syk in alphaIgM-stimulated human B cells assessed as CD86 expression after 1 hr incubation by flow cytometry, EC50=0.335μM.	24779514
Ramos	Function assay				Inhibition of Syk in anti IgM-stimulated human Ramos cells assessed as BLNK phosphorylation by cellular assay, IC50=0.457μM.	24726806
Rec1	Function assay	2.5 uM	6 hrs		Inhibition of BTK phosphorylation in human Rec1 cells at 2.5 uM incubated for 6 hrs by Western blotting method	25222877
Rec1	Function assay	2.5 uM	6 hrs		Inhibition of Syk phosphorylation in human Rec1 cells at 2.5 uM incubated for 6 hrs by Western blotting method	25222877
Rec1	Function assay	2.5 uM	6 hrs		Inhibition of Lyn phosphorylation in human Rec1 cells at 2.5 uM incubated for 6 hrs by Western blotting method	25222877
SJ-GBM2	qHTS assay				qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for SJ-GBM2 cells	29435139
A673	qHTS assay				qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for A673 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
NB-EBc1	qHTS assay				qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for NB-EBc1 cells	29435139
Saos-2	qHTS assay				qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for Saos-2 cells	29435139
OHS-50	qHTS assay				qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for OHS-50 cells	29435139
Rh41	qHTS assay				qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for Rh41 cells	29435139
Klicken Sie hier, um weitere experimentelle Daten zu Zelllinien anzuzeigen

Chemische Informationen, Lagerung & Stabilität (Chemical Information, Storage & Stability)

Molekulargewicht	628.63	Formel	C₂₂H₂₃FN₆O₅.C₆H₆O₃S	Lagerung (Ab dem Eingangsdatum)	3 Jahre-20°CPulver
CAS-Nr.	841290-81-1	SDF herunterladen		Lagerung von Stammlösungen	1 Jahr-80°Cin Lösungsmittel 1 Monat-20°Cin Lösungsmittel
Synonyme	R406 besylate			Smiles	CC1(C(=O)NC2=C(O1)C=CC(=N2)NC3=NC(=NC=C3F)NC4=CC(=C(C(=C4)OC)OC)OC)C.C1=CC=C(C=C1)S(=O)(=O)O

Löslichkeit (Solubility)

In vitro
Charge:

DMSO : 100 mg/mL (159.07 mM)
(Feuchtigkeitskontaminiertes DMSO kann die Löslichkeit verringern. Verwenden Sie frisches, wasserfreies DMSO.)

Water : Insoluble

Ethanol : 0 mg/mL

DMSO : 126 mg/mL (200.43 mM)
(Feuchtigkeitskontaminiertes DMSO kann die Löslichkeit verringern. Verwenden Sie frisches, wasserfreies DMSO.)

Ethanol : 8 mg/mL

Water : Insoluble

DMSO : 100 mg/mL (159.07 mM)
(Feuchtigkeitskontaminiertes DMSO kann die Löslichkeit verringern. Verwenden Sie frisches, wasserfreies DMSO.)

Ethanol : 38 mg/mL

Water : Insoluble

Molaritätsrechner

Masse	Konzentration	Volumen	Molekulargewicht
=	×	×

Verdünnungsrechner Molekulargewichtsrechner

In vivo Charge:
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 Corn oil Von Selleck Labs validiert. Sollten Sie Anpassungen an dieser Formulierung benötigen, kontaktieren Sie unser Verkaufsteam für kundenspezifische Tests.	0.500mg/ml (0.80mM)	Taking the 1 mL working solution as an example, add 50 μL of 120 mg/ml clear DMSO stock solution to 950 μL of corn oil and mix evenly. 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.

In-vivo-Formulierungsrechner (Klare Lösung)

Schritt 1: Geben Sie die untenstehenden Informationen ein (Empfohlen: Ein zusätzliches Tier zur Berücksichtigung von Verlusten während des Experiments)

Dosierung: mg/kg Durchschnittsgewicht der Tiere: g Dosiervolumen pro Tier:μL Anzahl der Tiere:

Schritt 2: Geben Sie die In-vivo-Formulierung ein (Dies ist nur der Rechner, keine Formulierung. Bitte kontaktieren Sie uns zuerst, wenn es im Abschnitt "Löslichkeit" keine In-vivo-Formulierung gibt.)

% DMSO + % + % Tween 80 + % ddH₂O

%DMSO+ %

Berechnungsergebnisse:

Arbeitskonzentration: mg/ml;

Methode zur Herstellung der DMSO-Stammlösung: mg Wirkstoff vorgelöst in μL DMSO ( Konzentration der Stammlösung mg/mL, Bitte kontaktieren Sie uns zuerst, wenn die Konzentration die DMSO-Löslichkeit der Wirkstoffcharge überschreitet. )

Methode zur Herstellung der In-vivo-Formulierung: Nehmen Sie μL DMSO Stammlösung, dann hinzufügenμL PEG300, mischen und klären, dann hinzufügenμL Tween 80, mischen und klären, dann hinzufügen μL ddH₂O, mischen und klären.

Methode zur Herstellung der In-vivo-Formulierung: Nehmen Sie μL DMSO Stammlösung, dann hinzufügen μL Maisöl, mischen und klären.

Hinweis: 1. Bitte stellen Sie sicher, dass die Flüssigkeit klar ist, bevor Sie das nächste Lösungsmittel hinzufügen.
2. Achten Sie darauf, das/die Lösungsmittel der Reihe nach hinzuzufügen. Sie müssen sicherstellen, dass die bei der vorherigen Zugabe erhaltene Lösung eine klare Lösung ist, bevor Sie mit der Zugabe des nächsten Lösungsmittels fortfahren. Physikalische Methoden wie Vortex, Ultraschall oder ein heißes Wasserbad können zur Unterstützung des Lösens verwendet werden.

Wirkmechanismus (Mechanism of Action)

Merkmale	Lead drug candidate for rheumatoid arthritis.
Targets/IC₅₀/Ki	Flt3 (Cell-free assay) Syk (Cell-free assay) 41 nM
In vitro	R406 is a potent inhibitor of immunoglobulin E (IgE)- and IgG-mediated activation of Fc receptor signaling. This compound inhibits the anti-IgE-induced production and release of LTC4 and cytokines and chemokines, including TNFα, IL-8, and GM-CSF. It inhibits phosphorylation of Syk substrate linker for activation of T cells in mast cells and B-cell linker protein/SLP65 in B cells. This chemical binds to the ATP binding pocket of Syk and inhibits its kinase activity as an ATP-competitive inhibitor with K_i of 30 nM. It blocks Syk-dependent FcR-mediated activation of monocytes/macrophages and neutrophils and Bcr-mediated activation of B lymphocytes. This compound significantly induces chronic lymphocytic leukemia (CLL) cell apoptosis in nurselike cells cocultures and blocks CCL3 and CCL4 secretion by CLL cells in response to B-cell antigen receptor (Bcr) triggering. It is a potent inhibitor of platelet signaling and functions initiated by FcγRIIA cross-linking by specific antibodies or by sera from HIT patients.
Kinase-Assay	In-Vitro-Fluoreszenzpolarisations-Kinase-Assay
Kinase-Assay	R406 wird seriell in DMSO verdünnt und anschließend in Kinase-Puffer (20 mM HEPES, pH 7,4, 5 mM MgCl₂, 2 mM MnCl₂, 1 mM DTT, 0,1 mg/mL acetyliertes BGG) auf 1 % DMSO verdünnt. ATP und Substrat werden im Kinase-Puffer bei Raumtemperatur zugegeben, was zu einer endgültigen DMSO-Konzentration von 0,2 % führt. Die Kinase-Reaktionen werden in einem Endvolumen von 20 mL durchgeführt, das 5 mM HS1-Peptid-Substrat und 4 mM ATP enthält, und durch Zugabe von 0,125 ng Syk in Kinase-Puffer gestartet. Die Reaktion wird für 40 Minuten bei Raumtemperatur inkubiert. Die Reaktion wird durch Zugabe von 20 mL PTK-Quench-Mix gestoppt, der EDTA/Anti-Phosphotyrosin-Antikörper (1X endgültig)/fluoreszierenden Phosphopeptid-Tracer (0,5X endgültig) enthält, verdünnt in FP-Verdünnungspuffer. Die Platte wird für 30 Minuten im Dunkeln bei Raumtemperatur inkubiert und anschließend auf einem Polarion-Fluoreszenzpolarisations-Plattenlesegerät gemessen. Die Daten werden unter Verwendung einer Kalibrierungskurve, die durch Wettbewerb mit dem im Tyrosine Kinase Assay Kit bereitgestellten Phosphopeptid-Wettbewerber erstellt wurde, in die Menge an vorhandenem Phosphopeptid umgerechnet. Zur IC50-Bestimmung wird diese Verbindung in elf Konzentrationen getestet und die Kurvenanpassung mittels nichtlinearer Regressionsanalyse durchgeführt.
In vivo	R406 reduces cutaneous reverse passive Arthus reaction by approximately 86% at 5 mg/kg in prophylactic treated mice. This compound also shows efficacy in inhibiting paw inflammation in antibody-induced arthritis mouse models. It does not adversely affect macrophage or neutrophil function in innate immune responses and has minimal functional immunotoxicity notwithstanding its lymphocytopenic effect.
Literatur	[1] https://pubmed.ncbi.nlm.nih.gov/16946104/ [2] https://pubmed.ncbi.nlm.nih.gov/19491390/ [3] https://pubmed.ncbi.nlm.nih.gov/21848694/ [4] https://pubmed.ncbi.nlm.nih.gov/17490694/

Anwendungen (Applications)

Methoden	Biomarker	Bilder	PMID
Western blot	p-AKT / T-AKT / p-mTOR / T-mTOR p-c-RAF / T-c-RAF p-MEK / T-MEK / p-ERK / T-ERK p-RPS6 / T-RPS6 / p-4E-BP1 / T-4E-BP1		23535559
Growth inhibition assay	Cell viability (GSC lines) Cell viability (U87, U251 cells)		31043589

Klinische Studieninformationen (Clinical Trial Information)

(Daten von https://clinicaltrials.gov, aktualisiert am 2024-05-22)

NCT-Nummer	Rekrutierung	Erkrankungen	Sponsor/Kooperationspartner	Startdatum	Phasen
NCT01725230	Completed	Rheumatoid Arthritis	AstraZeneca	November 2012	Phase 1
NCT01598571	Completed	Healthy	AstraZeneca	May 2012	Phase 1
NCT01387308	Completed	Healthy	AstraZeneca	August 2011	Phase 1
NCT01355354	Completed	Healthy Volunteers\|Rheumatoid Arthritis	AstraZeneca	June 2011	Phase 1

Häufig gestellte Fragen (Frequently Asked Questions)

Frage 1:
What’s the difference between S1533 and S2194?

Antwort:
S1533 and S2194 are two different forms of this compound. S1533 is the free base form, containing only its molecule without an acid added to it. S2194 has an additional C6H6O3S acid on it which makes the molecule a salt form. The free base and salt forms have same biology activities. Free base has a lower molecular weight and salt form has a better solubility in DMSO.

C1=C0/X	C1:	LOG(C1):
C2=C1/X	C2:	LOG(C2):
C3=C2/X	C3:	LOG(C3):
C4=C3/X	C4:	LOG(C4):
C5=C4/X	C5:	LOG(C5):
C6=C5/X	C6:	LOG(C6):
C7=C6/X	C7:	LOG(C7):
C8=C7/X	C8:	LOG(C8):

R406 Syk/FLT3 Inhibitor

Molekulargewicht: 628.63

Qualitätskontrolle (Quality Control)

Zellkultur, Behandlung & Arbeitskonzentration (Cell Culture, Treatment & Working Concentration)

Chemische Informationen, Lagerung & Stabilität (Chemical Information, Storage & Stability)

Löslichkeit (Solubility)

Molaritätsrechner

In-vivo-Formulierungsrechner (Klare Lösung)

Wirkmechanismus (Mechanism of Action)

Anwendungen (Applications)

Klinische Studieninformationen (Clinical Trial Information)

Häufig gestellte Fragen (Frequently Asked Questions)

Zellkultur, Behandlung & Arbeitskonzentration
(Cell Culture, Treatment & Working Concentration)