PHA-767491 HCl

別名:CAY10572, NMS 1116354

PHA-767491 (CAY10572, NMS 1116354) HCl is a potent ATP-competitive dual Cdc7/CDK9 inhibitor with IC50 of 10 nM and 34 nM in cell-free assays, respectively.It displays ~20-fold selectivity against CDK1/2 and GSK3-β, 50-fold selectivity against MK2 and CDK5, 100-fold selectivity against PLK1 and CHK2.

PHA-767491 HCl化学構造

CAS No. 942425-68-5

サイズ 価格(税別) 在庫状況
10mM (1mL in DMSO) JPY 29500 国内在庫あり
JPY 22000 国内在庫あり
JPY 55500 国内在庫あり

代表番号: 045-509-1970|電子メール:sales@selleck.co.jp
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製品安全説明書

現在のバッチを見る: 純度: 99.96%
99.96

PHA-767491 HCl関連製品

シグナル伝達経路

CDK阻害剤の選択性比較

阻害剤 Citation CDK1 CDK2 CDK3 CDK4 CDK5 CDK6 CDK7 CDK9 CLK Cdc CDK8 CDK12 CDK13 CDK19 CDK11 CDK/cyclin complexes その他
Roscovitine 124 ERK2
SNS-032 (BMS-387032) 76 GSK-3α
Dinaciclib 140
Flavopiridol (Alvocidib) 136
AT7519 52 GSK-3β
Flavopiridol (Alvocidib) HCl 60
JNJ-7706621 27 Aurora A,Aurora B,VEGFR2
PF-562271 Besylate 26 FAK,PYK2,FLT3
AZD5438 23
MK-8776 (SCH 900776) 75 Chk1
PF-562271 121 FAK,PYK2,FLT3
PHA-793887 13 GSK-3β
BS-181 HCl 16
A-674563 HCl 28 Akt1,PKA,GSK-3β
BMS-265246 12
PHA-767491 HCl 42 GSK-3β,MK2,PLK1
Milciclib 16 TrkA
BIO 36 GSK-3,TYK2,JAK3
R547 5
NU6027 4 ATR,DNA-PK
PF-562271 HCl 34 FAK,PYK2,FLT3
Riviciclib hydrochloride (P276-00) 6 GSK-3β
BAY 1000394 0
SRX3177 0 BRD4 BD1,PI3Kα,PI3Kδ
SY-5609 0
INX-315 0
TL12-186 0
Toyocamycin 0 XBP1
NSC 663284 0 NSD2
PF-07220060 (CDK4/6-IN-6) 0
CDK-IN-2 0
NVP-LCQ195 0
FN-1501 0 FLT3,CDK6/cyclin D1
1-Naphthyl PP1 hydrochloride 0 c-Abl,c-Fyn,v-Src
RGB-286638 free base 0 GSK-3β,TAK1,Jak2
CGP60474 1
CAN508 0
M2N12 0
Dalpiciclib 0
KB-0742 Dihydrochloride 0
CC-671 0 TTK
1-NM-PP1 1 c-Fyn-as1,v-Src-as1,CAMKII-as1
PF-06873600 3
Voruciclib 0
Fadraciclib (CYC065) 1
LY3405105 0
CDKI-73 1
NVP-2 1
Simurosertib 1
JSH-150 0
AS2863619 1
THZ2 0
SR-4835 1
Purvalanol B 0
Alsterpaullone 0 caspase-9,GSK-3β,GSK-3α
CDK2-IN-73 (CDK2-IN-4) 2
NSC95397 1 MKP-1
1-Naphthyl PP1(1-NA-PP1) 1 PKD3,PKD2,PKD1
Indirubin-3'-monoxime 1
BI-1347 0
THZ531 5
YKL-5-124 6
Enitociclib (BAY 1251152) 7
MC180295 1 CDK5-P25
Samuraciclib (ICEC0942) hydrochloride 3
NG 52 0
Bohemine 0
G1T38 0
CVT-313 5
SEL120 (SEL120-34A) hydrochloride 5
AZD4573 14
Atuveciclib (BAY-1143572) 6 GSK-3α,GSK3β
NU2058 1
MSC2530818 7
Senexin A 2
OTS964 7 TOPK
LY2857785 2
LDC4297 4
ON123300 3 ARK5,RET,Fyn
Kenpaullone 5 GSK-3β,ERK2,c-Src
K03861 (AUZ454) 14
THZ1 2HCl 32
AT7519 HCl 12 GSK-3β
Purvalanol A 17
Ro-3306 154 PKCδ,SGK,ERK
SU9516 4
XL413 28 Pim1,CK2
LDC000067 41
ML167 1
TG003 8
Inixaciclib 0
AZD8421 0
BLU-222 0
Avotaciclib trihydrochloride 0
Tagtociclib (PF-07104091) 1
Cirtuvivint 0 DYRK
(R)-CR8 trihydrochloride 0
BSJ-4-116 0
Indisulam 2 CA
Resibufogenin 2 RIP3,p-GSK3β,p-AKT
Cinobufagin 0 ATM,caspase-3,caspase-9
Motixafortide (BL-8040) 0 MCL-1,Bcl-2,ERK
LY3143921 hydrate 0
Sodium oxamate 19 ROS,LDHA
Apcin 5 APC/C
THAL-SNS-032 1 CRBN
BRD6989 1 IL-10
Aminopurvalanol A 0
CCT251545 3 Wnt
BSJ-03-123 0
Wogonin 3 N-acetyltransferase
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1. "+" indicates inhibitory effect. Increased inhibition is marked by a higher "+" designation. 2. "✔" indicates inhibitory effect, but without specific value.

Cell Data

Cell Lines Assay Type Concentration Incubation Time 活性情報 PMID
human HeLa cells Function assay 5 μM 24 h Induction of apoptosis in human HeLa cells assessed as appearance of PARP at 5 uM after 24 hrs 18469809
NHDF Function assay 5 μM 16 h Induction of cell cycle arrest in thymidine deficient NHDF assessed as DNA synthesis in S-phase at 5 uM after 16hrs FACS analysis in presence of serum 18469809
human SF268 cells Proliferation assay 72 h Antiproliferative activity against p53 deficient human SF268 cells after 72 hrs, IC50=0.86 μM 18469809
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生物活性

製品説明 PHA-767491 (CAY10572, NMS 1116354) HCl is a potent ATP-competitive dual Cdc7/CDK9 inhibitor with IC50 of 10 nM and 34 nM in cell-free assays, respectively.It displays ~20-fold selectivity against CDK1/2 and GSK3-β, 50-fold selectivity against MK2 and CDK5, 100-fold selectivity against PLK1 and CHK2.
特性 The first inhibitor that directly affects the mechanisms controlling initiation as opposed to elongation in DNA replication.
Targets
Cdc7 [1]
(Cell-free assay)
CDK9 [1]
(Cell-free assay)
GSK-3β [1]
(Cell-free assay)
CDK2 [1]
(Cell-free assay)
CDK1 [1]
(Cell-free assay)
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10 nM 34 nM 220 nM 240 nM 250 nM
In Vitro
In vitro

PHA-767491 displays approximately 20-fold selectivity for Cdk1, Cdk2 and GSK3-β, 50-fold selectivity for MK2 and Cdk5 and 100-fold selectivity for PLK1 and CHK2. PHA-767491 inhibits cell proliferation in a variety of human cell lines with IC50 of 0.86 μM for SF-268 to 5.87 μM for K562, and significantly induces apoptosis in a p53-independent manner in almost all cell lines in contrast with 5-FU  which only works in a few of cell lines. Unlike current DNA synthesis inhibitors, PHA-767491 treatment at 5 μM blocks the initiation of DNA replication but not replication fork progression, due to specific inhibition of Cdc7 kinase and Mcm2 phosphorylation at the Cdc7-dependent Ser40 site. [1] The up-regulated Mcl-1 levels in ABT-737-resistant OCI-LY1 and SU-DHL-4 cells can be significantly decreased by PHA-767491 treatment at 3 μM possibly due to the inhibition of Cdk9, leading to the restoration of the sensitivity to ABT-737. [2] The direct mitochondrial dependent pro-apoptosis effect of PHA-767491 is also observed when applied at 1 μM in quiescent chronic lymphocytic leukemia (CLL) cells through the similar mechanism with EC50 of 0.34-0.97 μM. While in proliferating CLL cells stimulated by CD154 and interleukin-4, PHA-767491 treatment at 5 μM abolishes DNA synthesis by inhibiting Cdc7 rather than triggering cell death. [3]

Kinase Assay In vitro kinase assays
The inhibition of Cdc7 and Cdk9 by PHA-767491 (IC50) is determined using the strong anion exchanger (Dowex 1-X8 resin, formate form)-based assay. For each enzyme, the absolute Km values for ATP and the specific substrate are initially determined, and each assay is then run at optimized ATP/33P-γ-ATP mix (2Km) and substrate (5Km) concentrations. Cdc7 kinase assay is performed in a buffer containing 50 mM Hepes pH 7.9, 15 mM MgCl2, 2 mM β- glycerylphosphate, 0.2 mg/mL BSA, 1 mM DTT, 3 μM Na3VO4, 2Km ATP/33P-γ-ATP mix, 5Km Mcm2 (aa 10-294), 37 nM of recombinant Cdc7/Dbf4 and increasing concentration of PHA-767491 in a final volume of 30 μL, and incubated for 1 hour at 25 °C. Cdk9 kinase assay is performed using 50 nM of recombinant Cdk9/cyclin T in 50 mM HEPES pH 7.5, 10 mM MgCl2, 1 mM DTT, 3 μM Na3VO4, 2Km ATP/33P-γ-ATP mix, 5Km RNA polymerase CDT peptide and increasing concentration of PHA-767491 in a final volume of 30 μL, and incubated for 1 hour at 25 °C. After incubation, an amount of 150 μL of resin/formate (pH 3.0) is added to stop the reaction and capture unreacted 33P-γ-ATP, separating it from the phosphorylated substrate in solution. After 1 hour of rest, a volume of 50 μL supernatant is transferred to Optiplate 96-well plates. After the additon of 150 μL of Microscint 40, the radioactivity is counted in the TopCount.
細胞実験 細胞株 HeLa, MCF7, HCT-116, U2OS, A2780, K562, SF-539, SF-268, Ovcar8, SW480, COLO205, HCT-15, Jurkat, PC3, and NHDF
濃度 Dissolved in DMSO, final concentrations ~ 20 μM
反応時間 24 or 72 hours
実験の流れ

Cells are exposed to PHA-767491 for 24 or 72 hours. Cells are lysed and the ATP content in the well, used as a measure of viable cells, is determined using a thermostable firefly luciferase–based assay. Activation of caspase-3 and caspase-7 is measured as a ratio between treated sample and untreated control with a luciferase-based assay, containing a specific proluminescent substrate. DNA replication is measured as incorporation of nucleotide analog BrdU into DNA by flow cytometry.

実験結果図 Methods Biomarkers 結果図 PMID
Western blot p-MCM2 / CDC7 RNA Pol II / p-RNA Pol II / Caspase-3 / PARP / Mcl-1 / XIAP / Bcl-xL / Bcl-2 / NOXA 24902048
In Vivo
In Vivo

Administration of PHA-767491 twice a day for 5 days significantly inhibits the growth of HL60 xenograft in a dose-dependent manner with TGI of 50% and 92% at dose of 20 mg/kg and 30 mg/kg, respectively, the effect of which is also marked in A2780, Mx-1, and HCT-116 xenograft models as well as the mammary carcinomas, and correlates with Cdc7 inhibition and subsequently decreased phosphorylation of Mcm2 at the Cdc7-dependent site Ser40 [1]

動物実験 動物モデル Female SCID mice subcutaneously implanted with HL60 cells, male Hsd, athymic nu-nu mice subcutaneously implanted with HCT116 cells, A2780 or Mx-1 cells, and female Sprague-Dawley rats with mammary carcinomas
投与量 ~50 mg/kg
投与経路 Intravenous or oral administration twice a day

化学情報

分子量 249.7 化学式

C12H11N3O.HCl

CAS No. 942425-68-5 SDF Download PHA-767491 HCl SDFをダウンロードする
Smiles C1CNC(=O)C2=C1NC(=C2)C3=CC=NC=C3.Cl
保管

In vitro
Batch:

DMSO : 24 mg/mL ( (96.11 mM); 吸湿したDMSOは溶解度を減少させます。新しいDMSOをご使用ください。)

Water : Insoluble

Ethanol : Insoluble

モル濃度計算器

in vivo
Batch:

Add solvents to the product individually and in order.

投与溶液組成計算機
Clear solution
5%DMSO 30% 2% 63%ddH2O
1.0mg/ml (4.00mM) Taking the 1 mL working solution as an example, add 50 μL of 20 mg/ml clarified DMSO stock solution to 300 μL of PEG300, mix evenly to clarify it; add 20 μL of Tween80 to the above system, mix evenly to clarify; then continue to add 630 μL of ddH2O to adjust the volume to 1 mL. The mixed solution should be used immediately for optimal results. 

実験計算

モル濃度計算器

質量 濃度 体積 分子量

投与溶液組成計算機(クリア溶液)

ステップ1:実験データを入力してください。(実験操作によるロスを考慮し、動物数を1匹分多くして計算・調製することを推奨します)

mg/kg g μL

ステップ2:投与溶媒の組成を入力してください。(ロット毎に適した溶解組成が異なる場合があります。詳細については弊社までお問い合わせください)

% DMSO % % Tween 80 % ddH2O
%DMSO %

計算結果:

投与溶媒濃度: mg/ml;

DMSOストック溶液調製方法: mg 試薬を μL DMSOに溶解する(濃度 mg/mL, 注:濃度が当該ロットのDMSO溶解度を超える場合はご連絡ください。 )

投与溶媒調製方法:Take μL DMSOストック溶液に μL PEG300,を加え、完全溶解後μL Tween 80,を加えて完全溶解させた後 μL ddH2O,を加え完全に溶解させます。

投与溶媒調製方法:μL DMSOストック溶液に μL Corn oil,を加え、完全溶解。

注意:1.ストック溶液に沈殿、混濁などがないことをご確認ください;
2.順番通りに溶剤を加えてください。次のステップに進む前に溶液に沈殿、混濁などがないことを確認してから加えてください。ボルテックス、ソニケーション、水浴加熱など物理的な方法で溶解を早めることは可能です。

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