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Dinaciclib (SCH 727965) CDK Remmer

Name: Dinaciclib (SCH 727965)
Brand: Selleck Chemicals
SKU: S2768
Rating: 5 (150 reviews)

Cat.Nr.: S2768

Dinaciclib is een nieuwe en krachtige CDK-remmer voor CDK2, CDK5, CDK1 en CDK9 met een IC50 van respectievelijk 1 nM, 1 nM, 3 nM en 4 nM in celvrije assays. Het blokkeert ook de incorporatie van thymidine (dThd) DNA. Dinaciclib induceert apoptose door de activering van caspases 8 en 9. Fase 3.

Dinaciclib (SCH 727965) CDK Remmer Chemical Structure

Chemische structuur

Moleculair gewicht: 396.49

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Kwaliteitscontrole (Quality Control)

Batch: Zuiverheid: 99.99%

99.99

Producten Vaak Samen Gebruikt Met Dinaciclib (SCH 727965)

MK-2206 Dihydrochloride

It and MK-2206 2HCl combination use dramatically blocks tumor growth and markedly reduces the number of metastatic lesions in the orthotopic Panc265/Panc253 models.

SCH772984

It and SCH772984 combination use results in a more significant reduction in tumor growth than either treatment alone in mice.

Gerelateerde doelwitten	HSP PD-1/PD-L1 ROCK Wee1 DNA/RNA Synthesis Microtubule Associated Ras KRas Aurora Kinase Casein Kinase
Overige CDK Inhibitoren	AS2863619 Ro-3306 SEL120 (SEL120-34A) hydrochloride INX-315 Tagtociclib (PF-07104091) PF-07220060 (CDK4/6-IN-6) AZD4573 ON123300 Enitociclib (BAY 1251152) Samuraciclib (ICEC0942) hydrochloride

Celkweek, behandeling & werkconcentratie
(Cell Culture, Treatment & Working Concentration)

Cellijnen	Assaytype	Concentratie	Incubatietijd	Activiteitsbeschrijving	PMID
CA46	Apoptosis Assay	100 nM	24 h	induces cell cycle arrest	25289887
Kasumi-1	Apoptosis Assay	100 nM	24 h	induces cell cycle arrest	25289887
U937	Function Assay	2/5/10 nM	3 h	blocks induction of XBP-1s and downstream targets	24362465
8226	Function Assay	2/5/10 nM	4 h	blocks induction of XBP-1s and downstream targets	24362465
H929	Function Assay	2/5/10 nM	4 h	blocks induction of XBP-1s and downstream targets	24362465
K562	Function Assay	1.5/3/8 nM	6 h	blocks induction of XBP-1s and downstream targets	24362465
BaF3/Bcr-abl	Function Assay	1.5/3/8 nM	6 h	blocks induction of XBP-1s and downstream targets	24362465
U937	Function Assay	2/10 nM	3 h	blocks induction of XBP-1s and downstream targets	24362465
1205Lu	Growth Inhibition Assay	10/30 nM	72 h	inhibits cell growth and survival	23527225
WM1366	Growth Inhibition Assay	10/30 nM	72 h	inhibits cell growth and survival	23527225
RD	Growth Inhibition Assay			IC50=8.2 nM	22315240
Rh41	Growth Inhibition Assay			IC50=10.5 nM	22315240
Rh18	Growth Inhibition Assay			IC50=10.5 nM	22315240
Rh30	Growth Inhibition Assay			IC50=9 nM	22315240
BT-12	Growth Inhibition Assay			IC50=8.5 nM	22315240
CHLA-266	Growth Inhibition Assay			IC50=7.3 nM	22315240
TC-71	Growth Inhibition Assay			IC50=3.9 nM	22315240
CHLA-9	Growth Inhibition Assay			IC50=8 nM	22315240
CHLA-10	Growth Inhibition Assay			IC50=6.3 nM	22315240
CHLA-258	Growth Inhibition Assay			IC50=9.9 nM	22315240
GBM2	Growth Inhibition Assay			IC50=6.5 nM	22315240
NB-1643	Growth Inhibition Assay			IC50=3.3 nM	22315240
NB-EBc1	Growth Inhibition Assay			IC50=7 nM	22315240
CHLA-90	Growth Inhibition Assay			IC50=7.5 nM	22315240
CHLA-136	Growth Inhibition Assay			IC50=9.8 nM	22315240
NALM-6	Growth Inhibition Assay			IC50=4.6 nM	22315240
COG-LL-317	Growth Inhibition Assay			IC50=6.5 nM	22315240
RS4;11	Growth Inhibition Assay			IC50=5.1 nM	22315240
MOLT-4	Growth Inhibition Assay			IC50=9.3 nM	22315240
CCRF-CEM	Growth Inhibition Assay			IC50=5.6 nM	22315240
Kasumi-1	Growth Inhibition Assay			IC50=4.5 nM	22315240
Karpas-299	Growth Inhibition Assay			IC50=3.9 nM	22315240
Ramos-RA1	Growth Inhibition Assay			IC50=7.9 nM	22315240
MIAPaCa-2	Growth Inhibition Assay		72 h	GI50=10 nM	21768779
Pa20C	Growth Inhibition Assay		72 h	GI50=20 nM	21768779
ML-1	Apoptosis Assay	1-1000 nM	4 h	induces apoptosis slightly	21768777
Cytotoxicity assay	MDA-MB-436		72 hrs	IC50 = 0.005 μM	23600925
Cytotoxicity assay	NCI-H929		72 hrs	IC50 = 0.005 μM	23600925
Cytotoxicity assay	MDA-MB-231		72 hrs	IC50 = 0.005 μM	23600925
Cytotoxicity assay	SK-ES-1		72 hrs	IC50 = 0.005 μM	23600925
Cytotoxicity assay	A673		72 hrs	IC50 = 0.005 μM	23600925
Cytotoxicity assay	SK-BR-3		72 hrs	IC50 = 0.005 μM	23600925
Cytotoxicity assay	MNNG-HOS		72 hrs	IC50 = 0.0055 μM	23600925
Cytotoxicity assay	SK-UT-1		72 hrs	IC50 = 0.006 μM	23600925
Cytotoxicity assay	U266		72 hrs	IC50 = 0.006 μM	23600925
Cytotoxicity assay	RPMI18226		72 hrs	IC50 = 0.009 μM	23600925
Cytotoxicity assay	SW872		72 hrs	IC50 = 0.0095 μM	23600925
Cytotoxicity assay	T47D		72 hrs	IC50 = 0.01 μM	23600925
Apoptosis assay	A673		24 hrs	EC50 = 0.011 μM	23600925
Cytotoxicity assay	MCF7		72 hrs	IC50 = 0.02 μM	23600925
Function assay	Sf9			IC50 = 0.072 μM	26741853
Function assay	sf9			IC50 = 0.002 μM	26851505
Function assay	Sf9		1 hr	IC50 = 0.001 μM	27171036
Function assay	Sf9		1 hr	IC50 = 0.001 μM	27171036
Function assay	Sf9		1 hr	IC50 = 0.001 μM	27171036
Function assay	Sf9		1 hr	IC50 = 0.001 μM	27171036
Function assay	Sf9		1 hr	IC50 = 0.003 μM	27171036
Function assay	Sf9		1 hr	IC50 = 0.003 μM	27171036
Function assay	Sf9		1 hr	IC50 = 0.004 μM	27171036
Function assay	Sf9		1 hr	IC50 = 0.004 μM	27171036
Function assay	Sf9	10 uM		IC50 = 0.004 μM	29329658
Function assay	Sf9		1 hr	IC50 = 0.001 μM	29853338
Function assay	Sf9		1 hr	IC50 = 0.001 μM	29853338
Function assay	Sf9		1 hr	IC50 = 0.003 μM	29853338
Function assay	Sf9		1 hr	IC50 = 0.004 μM	29853338
Antiproliferative assay	MOLM13		72 hrs	GI50 = 0.0033 μM	30253346
Antiproliferative assay	MEC1		72 hrs	GI50 = 0.0036 μM	30253346
Antiproliferative assay	MOLM14		72 hrs	GI50 = 0.0045 μM	30253346
Antiproliferative assay	COLO205		72 hrs	GI50 = 0.0068 μM	30253346
Antiproliferative assay	HL60		72 hrs	GI50 = 0.008 μM	30253346
Antiproliferative assay	Ramos		72 hrs	GI50 = 0.0086 μM	30253346
Antiproliferative assay	GISTT1		72 hrs	GI50 = 0.0088 μM	30253346
Antiproliferative assay	U937		72 hrs	GI50 = 0.01 μM	30253346
Antiproliferative assay	A431		72 hrs	GI50 = 0.011 μM	30253346
Antiproliferative assay	SKM1		72 hrs	GI50 = 0.011 μM	30253346
Antiproliferative assay	MEC2		72 hrs	GI50 = 0.011 μM	30253346
Antiproliferative assay	A375		72 hrs	GI50 = 0.011 μM	30253346
Antiproliferative assay	OCI-AML3		72 hrs	GI50 = 0.013 μM	30253346
Antiproliferative assay	BE(2)-M17		72 hrs	GI50 = 0.021 μM	30253346
Antiproliferative assay	CHO		72 hrs	GI50 = 0.16 μM	30253346
Function assay	NCI-H929	0.005 uM	24 hrs	Inhibition of CDK2-mediated Rb phosphorylation at Ser 807/811 in human NCI-H929 cells at 0.005 uM after 24 hrs by immunoblotting analysis	23600925
Function assay	A673	0.05 uM	24 hrs	Inhibition of CDK2-mediated Rb phosphorylation at Ser 807/811 in human A673 cells at 0.05 uM after 24 hrs by immunoblotting analysis	23600925
Apoptosis assay	MEC1	0.01 uM	24 hrs	Induction of apoptosis in human MEC1 cells assessed as decrease in MCL-1 level at 0.01 uM after 24 hrs by immunoblotting analysis	30253346
Apoptosis assay	HL60	0.01 uM	24 hrs	Induction of apoptosis in human HL60 cells assessed as decrease in MCL-1 level at 0.01 uM after 24 hrs by immunoblotting analysis	30253346
Apoptosis assay	MV4-11	0.01 uM	24 hrs	Induction of apoptosis in human MV4-11 cells assessed as decrease in c-MYC level at 0.01 uM after 24 hrs by immunoblotting analysis	30253346
Apoptosis assay	MEC1	0.01 uM	24 hrs	Induction of apoptosis in human MEC1 cells assessed as decrease in c-MYC level at 0.01 uM after 24 hrs by immunoblotting analysis	30253346
Apoptosis assay	MV4-11	0.01 uM	24 hrs	Induction of apoptosis in human MV4-11 cells assessed as decrease in MCL-1 level at 0.01 uM after 24 hrs by immunoblotting analysis	30253346
Apoptosis assay	HL60	0.01 uM	24 hrs	Induction of apoptosis in human HL60 cells assessed as decrease in c-MYC level at 0.01 uM after 24 hrs by immunoblotting analysis	30253346
Cytotoxicity assay	U2OS		96 hrs	IC50 = 0.006 μM	ChEMBL
Function assay	U2OS		1 hr	IC50 = 0.007 μM	ChEMBL
Klik om meer experimentele gegevens over de cellijn te bekijken

Chemische informatie, Opslag en Stabiliteit (Chemical Information, Storage & Stability)

Moleculair gewicht	396.49	Formule	C₂₁H₂₈N₆O₂	Opslag (Vanaf de ontvangstdatum)	3 jaar-20°Cpoeder
CAS-nr.	779353-01-4	SDF downloaden		Opslag van stamoplossingen	1 jaar-80°Cin oplosmiddel 1 maand-20°Cin oplosmiddel
Synoniemen	SCH727965, PS-095760			Smiles	CCC1=C2N=C(C=C(N2N=C1)NCC3=C[N+](=CC=C3)[O-])N4CCCCC4CCO

Oplosbaarheid (Solubility)

In vitro
Batch:

DMSO : 79 mg/mL (199.24 mM)
(Met vocht verontreinigde DMSO kan de oplosbaarheid verminderen. Gebruik verse, watervrije DMSO.)

Ethanol : 35 mg/mL

Water : 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%PEG 300 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.	25.000mg/ml (63.05mM)	Taking the 1 mL working solution as an example, add 50 μL of 500 mg/mL clarified DMSO stock solution to 400 μL PEG300, mix evenly to clarify; add 50 μL Tween-80 to the above system, mix evenly to clarify; Then continue to add 500 μL 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 (Mechanism of Action)

Targets/IC₅₀/Ki	CDK2 (Cell-free assay) 1 nM CDK5 (Cell-free assay) 1 nM CDK1 (Cell-free assay) 3 nM CDK9 (Cell-free assay) 4 nM
In vitro	Dinaciclib is also a potent DNA replication inhibitor that blocks thymidine (dThd) DNA incorporation in A2780 cells with IC50 of 4 nM. This compound strongly suppresses phosphorylation of Rb on Ser 807/811 at concentrations >6.25 nM, which is in agreement with the observation that 4 nM concentrations are required for 50% inhibition of dThd DNA incorporation in the same cell model. Significantly, complete suppression of Rb phosphorylation is correlated with the onset of apoptosis, as indicated by the appearance of the p85 PARP cleavage product in cells exposed to >6.25 nM of this chemical. It is active against a broad spectrum of human tumor cell lines. Addition of this compound during exposure also suppresses accumulation of γ-H2AX, in a dose-dependent manner. It inhibits melanoma cell proliferation, and drives melanoma cells into massive apoptosis. This chemical induces the apoptosis of several osteosarcoma cell lines including those resistant to doxorubicin. It attenuates the phosphorylation of RNAP II at serine 2 and the phosphorylation of the CDK inhibitor p27^Kip1 at threonine 187. Reductions in phosphorylation activity occurrs at 12 - 40 nM of this compound (4 to 16 hours post-addition). It also reduces the phosphorylation of Rb at serine 807/811. This chemical induces the apoptosis of mock- and p53-depleted U2OS cells to a similar extent.
Kinase Assay	Cyclin/CDK kinase assay
Kinase Assay	Recombinant cycline/CDK holo-enzymen worden gezuiverd uit Sf9-cellen die zijn gemanipuleerd om baculovirussen te produceren die een specifieke cycline of CDK tot expressie brengen. Cycline/CDK-complexen worden typisch verdund tot een uiteindelijke concentratie van 50 μg/mL in een kinase-reactiebuffer die 50 mM Tris-HCl (pH 8,0), 10 mM MgCl₂, 1 mM DTT en 0,1 mM natriumorthovanadaat bevat. Voor elke kinase-reactie worden 1 μg enzym en 20 μL van een 2-μM substraatoplossing (een biotinyleerd peptide afgeleid van histone H1) gemengd en gecombineerd met 10 μL van deze verdunde verbinding. De reactie wordt gestart door de toevoeging van 50 μL van 2 μM ATP en 0,1 μCi van ³³P-ATP. Kinase-reacties worden gedurende 1 uur bij kamertemperatuur geïncubeerd en gestopt door de toevoeging van 0,1% Triton X-100, 1 mM ATP, 5 mM EDTA en 5 mg/mL streptavidine-gecoate SPA-parels. SPA-parels worden opgevangen met behulp van een 96-well GF/B-filterplaat en een Filtermate universele oogster. De parels worden tweemaal gewassen met 2 M NaCl en tweemaal met 2 M NaCl dat 1% fosforzuur bevat. Het signaal wordt vervolgens gemeten met een TopCount 96-well vloeistofscintillatieteller.
In vivo	Dinaciclib i.p. administration at 8, 16, 32, and 48 mg/kg daily for 10 days results in tumor inhibition by 70%, 70%, 89%, and 96%, respectively. This compound's MED (minimum effective dose) appears to be <8 mg/kg. It is well tolerated, and the maximum body weight loss in the highest dosage group is 5%. This chemical has dose-dependent antitumor activity in vivo, and that nearly complete inhibition of tumor growth occurs at a dose level below the MTD (maximum tolerated dose). It has a short plasma half-life in mouse.
Referenties	[1] https://pubmed.ncbi.nlm.nih.gov/20663931/ [2] https://pubmed.ncbi.nlm.nih.gov/21321066/ [3] https://pubmed.ncbi.nlm.nih.gov/21358262/ [4] https://pubmed.ncbi.nlm.nih.gov/21490307/

Toepassingen (Applications)

Methoden	Biomarkers	PMID
Western blot	Mcl-1 / Bcl-2 / Bcl-xl / Bax / Bak / PUMA / Noxa Cleaved PARP / c-Myc Survivin RNAP II (P-Ser2/P-Ser5)	28714472
Growth inhibition assay	Cell viability Cell viability	27378523
Immunofluorescence	cyclin B1 / α-tubulin / Aurora A OCT4	28207834

Informatie klinische proef (Clinical Trial Information)

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

NCT-nummer	Rekrutering	Aandoeningen	Sponsor/Medewerkers	Startdatum	Fasen
NCT03484520	Terminated	Cancer - Acute Myeloid Leukemia	AbbVie\|Merck Sharp & Dohme LLC	July 23 2018	Phase 1
NCT01434316	Active not recruiting	Advanced Malignant Solid Neoplasm	National Cancer Institute (NCI)	November 1 2011	Phase 1

Veelgestelde vragen (Frequently Asked Questions)

Vraag 1:
I want to know how to reconstitute it for in vivo studies?

Antwoord:
It can be dissolved in 2% DMSO/30% PEG 300/ddH2O at 10 mg/ml as a clear solution for injection. And this compound in 15% Captisol at 8 mg/ml is a suspension for oral administration.

C1=C0/X	C1:	LOG(C1):
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C5=C4/X	C5:	LOG(C5):
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