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Silmitasertib (CX-4945) Caseïne Kinase 2-remmer

Name: Silmitasertib (CX-4945)
Brand: Selleck Chemicals
SKU: S2248
Rating: 5 (144 reviews)

Cat.Nr.S2248

Silmitasertib (CX-4945) is een krachtige en selectieve remmer van CK2 (caseïne kinase 2) met een IC50 van 1 nM in een celvrije test, hoewel het minder potent is tegen Flt3, Pim1 en CDK1 (inactief in een celgebaseerde test). Deze verbinding induceert autofagie en bevordert apoptose. Fase 1/2.

Silmitasertib (CX-4945) Casein Kinase remmer Chemical Structure

Chemische structuur

Moleculair gewicht: 349.77

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Kwaliteitscontrole

Batch: Zuiverheid: 99.96%

99.96

Gerelateerde doelwitten	Dehydrogenase HSP Transferase P450 (e.g. CYP17) PDE phosphatase PPAR Vitamin Carbohydrate Metabolism Mitochondrial Metabolism
Overige Casein Kinase Inhibitoren	Silmitasertib (CX-4945) sodium salt D 4476 TBB IC261 PF-670462 Ellagic Acid hydrate TTP 22 Longdaysin PF 4800567 (E/Z)-GO289

Celkweek, behandeling & werkconcentratie

Cellijnen	Assaytype	Concentratie	Incubatietijd	Formulering	Activiteitsbeschrijving	PMID
UM-SCC-1	Clonogenic Assay	0.5-5 μM	14 d	DMSO	inhibits clonogenic survival and sphere formation	25379016
U87-MG	Growth Inhibition Assay	1/5/10 μM	24/48/72 h	DMSO	inhibits cell growth both concentration and time dependently	25241897
MDA-MB-231	Function Assay	2/5/10 μM	4 h		inhibits serine 529 phosphorylation and the expression of IL-6, IL-8	25153725
MDA-MB-231	Function Assay	2/5/10 μM	4 h		decreases the constitutive phosphorylation of both p-S529-p65 and p-S129-Akt	25153725
HCT116	Apoptosis Assay	10 μM	24/48 h	DMSO	induces apoptosis	24686080
HCT116	Function Assay	10 μM	4 h	DMSO	causes ER-stress response over the p-eIF2α branch, but does not induce CHOP	24686080
ARPE-19	Function Assay	10 μM	4 h	DMSO	causes ER-stress response over the p-eIF2α branch, but does not induce CHOP	24686080
HCT116	Growth Inhibition Assay	10 μM	24-96 h	DMSO	inhibits cell growth time dependently	24686080
ARPE-19	Growth Inhibition Assay	10 μM	24-96 h	DMSO	inhibits cell growth time dependently	24686080
ARPE-19	Kinase Assay	5/10/20 μM	24/48 h		inhibits CK2 kinase activity at a concentration of 5 μM	24686080
SUP-B15	Apoptosis Assay	6/10 μM	48 h		induces apoptosis	24561792
Nalm6	Apoptosis Assay	6/10 μM	48 h		induces apoptosis	24561792
SUP-B15	Function Assay	10/20 μM	24 h		results in decreased PTEN phosphorylation at the CK2 target residue S380 and concomitant downregulation of PTEN protein expression	24561792
Nalm6	Function Assay	10/20 μM	24 h		results in decreased PTEN phosphorylation at the CK2 target residue S380 and concomitant downregulation of PTEN protein expression	24561792
C2C12	Function Assay	3 μM	12/24/48 h		inhibits the expression of osteoclast differentiation markers and Akt phosphorylation	24293011
MOLT-4	Apoptosis Assay	5 μM	24/48 h		induces apoptosis	24253024
DND-41	Apoptosis Assay	5 μM	24/48 h		induces apoptosis	24253024
ALL-SIL	Apoptosis Assay	5 μM	24/48 h		induces apoptosis	24253024
DND-41	Growth Inhibition Assay	1-10 μM	48 h		IC50=9 μM	24253024
HPB-ALL	Growth Inhibition Assay	1-10 μM	48 h		IC50=6.1 μM	24253024
ALL-SIL	Growth Inhibition Assay	1-10 μM	48 h		IC50=5.7 μM	24253024
PF-382	Growth Inhibition Assay	1-10 μM	48 h		IC50=4.5 μM	24253024
MOLT-4	Growth Inhibition Assay	1-10 μM	48 h		IC50=5.7 μM	24253024
CEM-S	Growth Inhibition Assay	1-10 μM	48 h		IC50=4.6 μM	24253024
CEM-R	Growth Inhibition Assay	1-10 μM	48 h		IC50=4 μM	24253024
Jurkat	Growth Inhibition Assay	1-10 μM	48 h		IC50=4.9 μM	24253024
Rec-1	Growth Inhibition Assay	0-40 μM	48 h		IC50=1.46 µM	24086494
Jeko-1	Growth Inhibition Assay	0-40 μM	48 h		IC50=2.4 µM	24086494
INA-6	Growth Inhibition Assay	0-40 μM	48 h		IC50=2.42 µM	24086494
U-266	Growth Inhibition Assay	0-40 μM	48 h		IC50=19.8 µM	24086494
A549	Function Assay	3 μM	48 h		inhibits TGF-β1-induced activation of Smad and expression of Snail and Twist	24023938
A549	Function Assay	10 μM	12/24/48 h		inhibits TGF-β1-induced migration and invasion	24023938
R-LAMA84	Growth Inhibition Assay	2.5-10 μM	48 h	DMSO	inhibits cell growth concentration dependently	24012109
S-LAMA84	Growth Inhibition Assay	2.5-10 μM	48 h	DMSO	inhibits cell growth concentration dependently	24012109
R-LAMA84	Function Assay	3 μM	24 h	DMSO	reduces CK2 activity	24012109
S-LAMA84	Function Assay	3 μM	24 h	DMSO	reduces CK2 activity	24012109
A549	Function Assay	1/10 μM	48 h	DMSO	leads to a dose-dependent decrease in Notch reporter activity	23651443
H1299	Growth Inhibition Assay	0-30 μM	72 h	DMSO	IC50=1.80 μM, inhibits cell growth concentration dependently	23651443
A549	Growth Inhibition Assay	0-30 μM	72 h	DMSO	IC50=4.15 μM, inhibits cell growth concentration dependently	23651443
LNCap	Growth Inhibition Assay	0-30 μM	4 d		IC50=4.59 μM	22832316
H2170	Function Assay	10 μM	4-24 h		enhances apoptosis with	22387988
A431	Function Assay	10 μM	4-24 h		enhances apoptosis with	22387988
H2170	Function Assay	10 μM	30 min		attenuates PI3K-Akt-mTOR signaling	22387988
A431	Function Assay	10 μM	30 min		attenuates PI3K-Akt-mTOR signaling	22387988
UM-SCC-46	Clonogenic Assay	0.5-5 μM	14 d	DMSO	inhibits clonogenic survival and sphere formation	25379016
H28	Growth Inhibition Assay	0.01-30 μM	72 h	DMSO	IC50=7.2 μM	25422081
H2052	Growth Inhibition Assay	0.01-30 μM	72 h	DMSO	IC50=2.0 μM	25422081
PC9/GR	Function Assay	5 µM	48 h		induces autophagy	25486409
PC9/ER	Function Assay	5 µM	48 h		induces autophagy	25486409
H1299	Growth Inhibition Assay	1/5/10 μM	72 h		inhibits cell growth concentration dependently	25750308
Calu-1	Growth Inhibition Assay	1/5/10 μM	72 h		inhibits cell growth concentration dependently	25750308
H358	Growth Inhibition Assay	1/5/10 μM	72 h		inhibits cell growth concentration dependently	25750308
H1299	Apoptosis Assay	10 μM	72 h		induces apoptosis	25750308
Calu-1	Apoptosis Assay	10 μM	72 h		induces apoptosis	25750308
H358	Apoptosis Assay	10 μM	72 h		induces apoptosis	25750308
NU-DUL	Growth Inhibition Assay	5-25 μM	48 h		inhibits cell growth concentration dependently	25788269
Oci Ly 3	Growth Inhibition Assay	5-25 μM	48 h		inhibits cell growth concentration dependently	25788269
Oci Ly 10	Growth Inhibition Assay	5-25 μM	48 h		inhibits cell growth concentration dependently	25788269
Oci Ly 1	Growth Inhibition Assay	5-25 μM	48 h		inhibits cell growth concentration dependently	25788269
Oci Ly 18	Growth Inhibition Assay	5-25 μM	48 h		inhibits cell growth concentration dependently	25788269
Oci Ly 19	Growth Inhibition Assay	5-25 μM	48 h		inhibits cell growth concentration dependently	25788269
Raji	Growth Inhibition Assay	5-25 μM	48 h		inhibits cell growth concentration dependently	25788269
UM-SCC1	Growth Inhibition Assay	0.1-30 μM	1-5 d		IC50=4.1 μM	25798061
UM-SCC46	Growth Inhibition Assay	0.1-30 μM	1-5 d		IC50=3.4 μM	25798061
UM-SCC1	Function Assay	0.5/4/10 μM	72 h		down-regulates the expression of NF-ĸB, Bcl-XL and up-regulates the expression of p53, p21, AP-1 and IL-8 concentration dependently	25798061
UM-SCC46	Function Assay	0.5/4/10 μM	72 h		down-regulates the expression of NF-ĸB, Bcl-XL, p53, p21, AP-1 and up-regulates the expression IL-8 concentration dependently	25798061
HEK293	Kinase Assay	0.5 μM	15 min	DMSO	reduces CK2 kinase activity	25887626
Hela	Kinase Assay	0.5 μM	15 min	DMSO	reduces CK2 kinase activity	25887626
LAMA84	Kinase Assay	0.5 μM	15 min	DMSO	reduces CK2 kinase activity	25887626
HEK293	Function Assay	3 μM	5 h	DMSO	CK2 phosphorylates eIF3j at Ser127	25887626
HDMEC	Kinase Assay	1-50 μM	5 h	DMSO	decreases CK2 kinase activity without affecting cell viability	26189586
HDMEC	Function Assay	50 μM	1/5 h	DMSO	decreases the nuclear signal of phosphorylated p65 in TNF-α-stimulated HDMEC	26189586
A549	Function Assay	3/10 μM	48 h		suppresses the micropillar-induced expression of p-FAK	26318800
platelets	Kinase Assay	1/5/10 μM	0.5 h	DMSO	reduces CK2 kinase activity and platelet aggregation	26381437
HDMEC	Kinase Assay	0.25/0.5/1 μM	24 h	DMSO	reduces CK2 kinase activity, vWF expression and secretion	26381437
HDMEC	Function Assay	0.25/0.5/1 μM	24 h	DMSO	reduces expression of VCAM-1 but not ICAM-1	26381437
HDMEC	Function Assay	1 μM	24 h	DMSO	affects subcellular localization of NFATc1 and phospho-p65	26381437
Jurkat	Function assay				Inhibition of CK2 in human Jurkat cells assessed as inhibition of [gamma33P]ATP incorporation into substrate by luminescence assay, IC50 = 0.1 μM.	21174434
MIAPaCa2	Antiproliferative assay		4 days		Antiproliferative activity against human MIAPaCa2 cells after 4 days by alamar blue assay, IC50 = 1.1 μM.	21174434
PC3	Antiproliferative assay		4 days		Antiproliferative activity against human PC3 cells after 4 days by alamar blue assay, IC50 = 2.1 μM.	21174434
HCT116	Antiproliferative assay		4 days		Antiproliferative activity against human HCT116 cells after 4 days by alamar blue assay, IC50 = 2.2 μM.	21174434
H1299	Antiproliferative assay		4 days		Antiproliferative activity against human H1299 cells after 4 days by alamar blue assay, IC50 = 2.4 μM.	21174434
Jurkat	Antiproliferative assay		4 days		Antiproliferative activity against human Jurkat cells after 4 days by alamar blue assay, IC50 = 2.5 μM.	21174434
A549	Antiproliferative assay		4 days		Antiproliferative activity against human A549 cells after 4 days by alamar blue assay, IC50 = 3 μM.	21174434
A375	Antiproliferative assay		4 days		Antiproliferative activity against human A375 cells after 4 days by alamar blue assay, IC50 = 3.9 μM.	21174434
BxPC3	Antiproliferative assay		4 days		Antiproliferative activity against human BxPC3 cells after 4 days by alamar blue assay, IC50 = 4.4 μM.	21174434
LNCAP	Antiproliferative assay		4 days		Antiproliferative activity against human LNCAP cells after 4 days by alamar blue assay, IC50 = 4.7 μM.	21174434
K562	Antiproliferative assay		4 days		Antiproliferative activity against human K562 cells after 4 days by alamar blue assay, IC50 = 5.3 μM.	21174434
MDA-MB-231	Antiproliferative assay		4 days		Antiproliferative activity against human MDA-MB-231 cells after 4 days by alamar blue assay, IC50 = 6.4 μM.	21174434
MCF7	Antiproliferative assay		4 days		Antiproliferative activity against human MCF7 cells after 4 days by alamar blue assay, IC50 = 8.9 μM.	21174434
Hs 578T	Antiproliferative assay		4 days		Antiproliferative activity against human Hs 578T cells after 4 days by alamar blue assay, IC50 = 13.1 μM.	21174434
HCT116	Antiproliferative assay		72 hrs		Antiproliferative activity against human HCT116 cells after 72 hrs by MTS assay, IC50 = 5.2 μM.	22339433
MCF7	Antiproliferative assay		72 hrs		Antiproliferative activity against human MCF7 cells after 72 hrs by MTS assay, IC50 = 6.5 μM.	22339433
A549	Antiproliferative assay		72 hrs		Antiproliferative activity against human A549 cells after 72 hrs by MTS assay, IC50 = 8.2 μM.	22339433
MV4-11	Antiproliferative assay		1 to 3 days		Antiproliferative activity against human MV4-11 cells after 1 to 3 days by MTS assay, CC50 = 3 μM.	23711832
U937	Antiproliferative assay		1 to 3 days		Antiproliferative activity against human U937 cells after 1 to 3 days by MTS assay, CC50 = 4.2 μM.	23711832
Jurkat	Antiproliferative assay		1 to 3 days		Antiproliferative activity against human Jurkat cells after 1 to 3 days by MTS assay, CC50 = 4.5 μM.	23711832
K562	Antiproliferative assay		1 to 3 days		Antiproliferative activity against human K562 cells after 1 to 3 days by MTS assay, CC50 = 7 μM.	23711832
Sf9	Function assay				Inhibition of CDK2/cyclin E (unknown origin) expressed in Sf9 cells using histone H1 as substrate in presence of [gamma33P]ATP, IC50 = 1.8 μM.	24681986
A549	Cytotoxicity assay		72 hrs		Cytotoxicity against human A549 cells after 72 hrs by MTS assay, CC50 = 9.9 μM.	26850376
Sf21	Function assay		90 mins		Inhibition of recombinant human full length N-terminal His6-tagged CK2alpha expressed in Sf21 insect cells using CK2tide as substrate treated for 20 mins measured after 90 mins in presence of MgCl2 by caliper mobility shift assay, IC50 = 0.003 μM.	29559278
Vero E6	Antiviral assay		48 h		IC50 for antiviral activity against SARS-CoV-2 in the Vero E6 cell line at 48 h by immunofluorescence-based assay (detecting the viral NP protein in the nucleus of the Vero E6 cells)., IC50 = 3.89045 μM.	32353859
A549	Function assay	30 uM	48 hrs		Inhibition of CK2-mediated MMP2 activation in human A549 cells at 30 uM after 48 hrs by gelatin-zymography	24012124
A549	Function assay	10 uM	15 to 30 mins		Inhibition of CK2-mediated ERK phosphorylation in human A549 cells at 10 uM after 15 to 30 mins by Western blot method	24012124
A549	Function assay	1 to 10 uM	24 hrs		Inhibition of CK2-mediated MT1-MMP expression in human A549 cells at 1 to 10 uM after 24 hrs by Western blot method	24012124
A549	Function assay	10 uM			Inhibition of CK2-mediated ERK phosphorylation in human A549 cells at 10 uM by Western blot method	24012124
A549	Function assay	10 uM	24 hrs		Inhibition of CK2-mediated AKT phosphorylation in human A549 cells at 10 uM after 24 hrs by Western blot method	24012124
A549	Function assay	10 uM	4 to 24 hrs		Inhibition of CK2-mediated AKT phosphorylation in human A549 cells at 10 uM after 4 to 24 hrs by Western blot method	24012124
U-2 OS	qHTS assay				qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for U-2 OS cells	29435139
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
Saos-2	qHTS assay				qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for Saos-2 cells	29435139
BT-37	qHTS assay				qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for BT-37 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
BT-12	qHTS assay				qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for BT-12 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
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
SJ-GBM2	qHTS assay				qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for SJ-GBM2 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
LAN-5	qHTS assay				qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for LAN-5 cells	29435139
Rh18	qHTS assay				qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for Rh18 cells	29435139
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Chemische informatie, Opslag en Stabiliteit

Moleculair gewicht	349.77	Formule	C₁₉H₁₂ClN₃O₂	Opslag (Vanaf de ontvangstdatum)	3 jaar-20°Cpoeder
CAS-nr.	1009820-21-6	SDF downloaden		Opslag van stamoplossingen	1 jaar-80°Cin oplosmiddel 1 maand-20°Cin oplosmiddel
Synoniemen	N/A			Smiles	C1=CC(=CC(=C1)Cl)NC2=NC3=C(C=CC(=C3)C(=O)O)C4=C2C=CN=C4

Oplosbaarheid

In vitro
Batch:

DMSO : 70 mg/mL (200.13 mM)
(Met vocht verontreinigde DMSO kan de oplosbaarheid verminderen. Gebruik verse, watervrije DMSO.)

Water : Insoluble

Ethanol : Insoluble

Molariteitscalculator

Massa	Concentratie	Volume	Moleculair gewicht
=	×	×

Verdunningscalculator Moleculair gewicht calculator

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.	1.750mg/ml (5.00mM)	Taking the 1 mL working solution as an example, add 50 μL of 35 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 clarify; 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 Formuleringscalculator (Heldere oplossing)

Stap 1: Voer de onderstaande informatie in (Aanbevolen: Een extra dier voor het geval van 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 het gedeelte Oplosbaarheid.)

% DMSO + % + % Tween 80 + % ddH₂O

%DMSO+ %

Berekeningsresultaten:

Werkconcentratie: mg/ml;

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

Methode voor het bereiden van in vivo formulering: Neem μL DMSO mastervloeistof, voeg vervolgens toeμL PEG300, mengen en helder maken, voeg vervolgens toeμL Tween 80, mengen en helder maken, voeg vervolgens toe μL ddH₂O, mengen en helder maken.

Methode voor het bereiden van in vivo formulering: Neem μL DMSO mastervloeistof, voeg vervolgens toe μL Maïsolie, mengen en helder maken.

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. Fysische methoden zoals vortexen, echografie of een warmwaterbad kunnen worden gebruikt om het oplossen te bevorderen.

Werkingsmechanisme

Kenmerken	First clinical inhibitor of CK2.
Targets/IC₅₀/Ki	CK2 (Cell-free assay) 1 nM
In vitro	Silmitasertib (CX-4945) is selectief voor CK2, aangezien het slechts 7 van de 238 kinasen met meer dan 90% remt bij een concentratie van 0,5 μM, wat 500 keer groter is dan de IC50 van CK2. Hoewel deze verbinding in celvrije systemen FLT3, PIM1 en CDK1 remt met IC50 van respectievelijk 35 nM, 46 nM en 56 nM, is behandeling met 10 μM inactief tegen FLT3, PIM1 en CDK1 in celgebaseerde functionele assays. Het vertoont een breed spectrum aan antiproliferatieve activiteit, en de borstkankercellijnen vertonen het breedste bereik van gevoeligheid ervoor met EC50 van 1,71-20,01 μM. De antiproliferatieve activiteit van CX-4945 correleert met CK2α mRNA- en eiwitniveaus, maar niet met de katalytische CK2α'-subeenheid, de regulerende CK2β-subeenheid en de PI3K/Akt- of PTEN-mutatiestatus. Het remt PI3K/Akt-signalering door de fosforylering van Akt op Serine 129 door CK2 direct te blokkeren in plaats van door activering van PTEN. Behandeling met deze verbinding veroorzaakt verminderde fosforylering van p21 (T145), verhoogde niveaus van totaal p21 en p27, en inductie van caspase 3/7-activiteit. Het induceert een G2/M-celcyclusarrest in BT-474-cellen en een G1-arrest in BxPC-3-cellen. Deze verbinding remt HUVEC-proliferatie, -migratie en -buisvorming met IC50 van respectievelijk 5,5 μM, 2 μM en 4 μM. Onder hypoxische omstandigheden in BT-474- en BxPC-3-cellen voorkomt het de downregulatie van p53 en pVHL en vermindert het de activering van HIF-1α-transcriptie. Het remt krachtig de endogene intracellulaire CK2-activiteit met een IC50 van 0,1 μM in Jurkat-cellen.
Kinase Assay	CK2 Kinase Test
Kinase Assay	Silmitasertib (CX-4945) wordt in een volume van 10 μL toegevoegd aan een reactiemengsel bestaande uit 10 μL assay-verdunningsbuffer (ADB; 20 mM MOPS, pH 7,2, 25 mM β-glycerolfosfaat, 5 mM EGTA, 1 mM natriumorthovanadaat en 1 mM dithiothreitol), 10 μL substraatpeptide (RRRDDDSDDD, opgelost in ADB in een concentratie van 1 mM), 10 μL recombinant humaan CK2 (ααββ-holo-enzym, 25 ng opgelost in ADB). Reacties worden geïnitieerd door de toevoeging van 10 μL ATP-oplossing (90% 75 mM MgCl₂, 75 μM ATP (uiteindelijke ATP-concentratie=15 μM) opgelost in ADB; 10% [γ-³³P]ATP (stock 1 mCi/100 μL; 3000 Ci/mM en gedurende 10 minuten gehandhaafd bij 30 °C. De reacties worden geblust met 100 μL 0,75% fosforzuur en vervolgens overgebracht naar en gefilterd door een fosfocellulose filterplaat. Na het vijfmaal wassen van elke put met 0,75% fosforzuur, wordt de plaat gedurende 5 minuten onder vacuüm gedroogd en, na de toevoeging van 15 μL scintillatievloeistof aan elke put, wordt de resterende radioactiviteit gemeten met een Wallac luminescentieteller. De IC50-waarden voor deze verbinding zijn afgeleid van acht concentraties over een bereik van 0,0001 μM tot 1 μM.
In vivo	Orale toediening van Silmitasertib (CX-4945) in een dosis van 25 mg/kg of 75 mg/kg tweemaal daags vertoont een potente antitumoractiviteit in het BT-474-model, met een TGI van respectievelijk 88% en 97%, waarbij 2 van de 9 dieren in elke groep meer dan 50% reductie in tumorgrootte vertonen vergeleken met het initiële tumorvolume. In het BxPC-3-model toont behandeling met deze verbinding in een dosis van 75 mg/kg tweemaal daags een TGI van 93%, waarbij 3 dieren aan het einde van de behandelperiode geen bewijs van resterende tumor vertonen. In het PC3-xenograftmodel veroorzaakt toediening ervan in doses van 25 mg/kg, 50 mg/kg of 75 mg/kg tumorremming met een TGI van respectievelijk 19%, 40% en 86%.
Referenties	[1] https://pubmed.ncbi.nlm.nih.gov/21159648/ [2] https://pubmed.ncbi.nlm.nih.gov/21174434/ [3] https://pubmed.ncbi.nlm.nih.gov/22267551/ [4] https://pubmed.ncbi.nlm.nih.gov/22387988/

Toepassingen

Methoden	Biomarkers	PMID
Western blot	p-S6K1(T389) / S6K1 / p-S6(S235/236) / S6 p-AKT(S129) / p-AKT(T308) / p-AKT(S473) / AKT / p-ERK / ERK / TP53 / p-p21(Th145) / p21 / Bcl-xl p-Smad2 (Cytosol) / Smad2/3 (Cytosol) / Smad2/3 (Nucleus) / Twist / Snail	30683840
Immunofluorescence	β-catenin E-cadherin / Vimentin	24023938
Growth inhibition assay	Cell viability	30316146

Informatie klinische proef

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

NCT-nummer	Rekrutering	Aandoeningen	Sponsor/Medewerkers	Startdatum	Fasen
NCT05817708	Completed	COVID-19	Senhwa Biosciences Inc.	November 7 2022	Phase 1
NCT04668209	Terminated	Coronavirus	University of Arizona\|Senhwa Biosciences Inc.	January 21 2021	Phase 2
NCT04663737	Completed	Covid19	Chris Recknor MD\|Senhwa Biosciences Inc.	December 3 2020	Phase 2
NCT03904862	Suspended	Medulloblastoma Childhood	Pediatric Brain Tumor Consortium\|National Cancer Institute (NCI)\|American Lebanese Syrian Associated Charities (ALSAC)	July 25 2019	Phase 1\|Phase 2
NCT02128282	Completed	Cholangiocarcinoma	Senhwa Biosciences Inc.	June 2014	Phase 1\|Phase 2

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Vraag 1:
How to reconstitute it (S2248) for in vivo uses?

Antwoord:
For injection, it can be dissolved in 2% DMSO+30% PEG 300+2% Tween 80+ddH2O at 5mg/ml clearly. When making the solution, please dissolve this compound in DMSO clearly first. If it dissolves not readily, please sonicate and warm the solution in water bath at about 45-50℃. Then add PEG and Tween. After they mixed well, dilute with water. For oral gavage, it can be dissolved in 1% CMC Na at 30mg/ml as a homogeneous suspension. This is a common formulation for oral gavage, and is convenience to prepare.

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