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CAS No.: 891494-63-6

SCH900776 Catalog No. CSN16049

Synonyms: MK-8776

SCH 900776 (MK-8776) is a selective and highly potent CHK1 inhibitor with IC50 value of 3nM, modest to CDK2 and Chk2 with much higher IC50 values of 160nM and 1.5uM, respectively.

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靶点选择性

生物活性

实验方案

技术信息

生物活性

靶点 CDK2

IC50:160nM Chk1

IC50:3nM Chk2

IC50:1500nM
描述Chk1 (Checkpoint kinase 1), an important serine/threonine kinase, is responding to DNA damage and stall DNA replication. Chk1 plays a key role in maintaining the replication fork viability during exposure to DNA antimetabolites. Inhibition of Chk1 will lead to accumulation of double-strand DNA breaks and cell death in human tumor cell lines exposure to anti-metabolite. SCH 900776 (MK-8776) is a selective and highly potent CHK1 inhibitor with IC50 value of 3 nM (measured by kinase assays), modest to CDK2 and Chk2 with much higher IC50 values of 160 nM and 1.5 μM, respectively. Treatment with 8 - 500 nM of SCH 900776 for 2h led to dose-dependent accumulation of DNA double-strand breaks induced by hydroxyurea in U2OS cells (measured by g-H2AX, a biomarker of DNA double-strand breaks). Consistent with that, 0.06 – 2 μM SCH 900776 for 2h caused decreased level of p-Ser296 site of Chk1 (an autophosphorylation site of Chk1) in U2OS cells exposure to hydroxyurea. SCH 900776 can induce a dose-dependent loss of DNA replication capability (measured by BrdU positive cells number) after the hydroxyurea exposure. An increase in the sub-G1 population was also observed, suggesting the cell death within the culture. Consistent with that, SCH 900776 exposure can enhance apoptosis for at least 48h following release from hydroxyurea blockade. Intraperitoneally injection of 8 - 32 mg/kg SCH-900776, 30 minutes after gemcitabine (150 mg/kg) 3 cycles of treatment on every fifth day, can lead to enhanced tumor pharmacodynamic and regression responses relative to either agent alone in the A2780 xenografted models^[1]. Up to now, a phase I study of SCH-900776 in combination with gemcitabine in solid tumours and lymphoma has been completed^[2].
作用机制SCH-900776 is an ATP competitive inhibitor^[2].
细胞研究

Cell Data

Cell Lines	Concentration	Assay Type	Time	Activity Description	Data Sources
A2058	37.5-300 nM	Cell Viability Assay	72 h	reduces the MK-1775 EC50 by 5-fold to an average of 45 nM	23148684
A498	200/2000 nM	Growth Inhibition Assay	24 h	decreases the IC50 of Gemcitabine	24359526
AsPC-1	200/2000 nM	Growth Inhibition Assay	24 h	decreases the IC50 of Gemcitabine	24359526

动物研究

剂量

Mice^[1] (i.p.): min = 4 mg/kg, max = 50 mg/kg

给药途径

i.p.

动物药代数据

Animal	Nude mice^[1]
Dose	10 - 100 (mg/kg)
Administration	i.p.
C_max	0.56 - 19 (μM)
T_max	1 h
AUC	0.9 - 57 (μM·hr)

临床研究

NCT号	适应症或疾病	临床期	招募状态	预计完成时间	地点
NCT01521299	Advanced Solid Tumors	Phase 1	Withdrawn(Insufficient populat... more >>ion of eligible patients.) Collapse <<	December 2013	-
NCT00907517	Myelogenous Leukemia, Acute ... more >> Leukemia, Lymphocytic, Acute Leukemia, Lymphoblastic, Acute, Philadelphia-Positive Myelogenous Leukemia, Chronic, Aggressive Phase Collapse <<	Phase 1	Terminated	-	-
NCT00907517	-	-	Terminated	-	-

更多
参考文献

[1] Guzi TJ, Paruch K, et al. Targeting the replication checkpoint using SCH 900776, a potent and functionally selective CHK1 inhibitor identified via high content screening. Mol Cancer Ther. 2011 Apr;10(4):591-602.
[2] Matthews TP, Jones AM, et al. Structure-based design, discovery and development of checkpoint kinase inhibitors as potential anticancer therapies. Expert Opin Drug Discov. 2013 Jun;8(6):621-40.

实验方案

计算器摩尔计算器总药量计算器工作液计算器
储存液制备
- 1 mg
- 5 mg
- 10 mg
- 1 mM
- 2.6578 mL
- 13.2889 mL
- 26.5778 mL
- 5 mM
- 0.5316 mL
- 2.6578 mL
- 5.3156 mL
- 10 mM
- 0.2658 mL
- 1.3289 mL
- 2.6578 mL

技术信息

CAS号

891494-63-6

储存条件

粉末: Keep in dark place,Inert atmosphere,2-8°C

液体: -20°C:3-6 月 -80°C:12月

分子式

C15H18BrN7

运输

蓝冰

分子量

376.25

别名

MK-8776

溶解度

DMSO	34.67 mg/mL (92.1 mM)
Water	insoluble

动物实验配方

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Cell Lines	Concentration	Assay Type	Time	Activity Description	Data Sources

A2058	37.5-300 nM	Cell Viability Assay	72 h	reduces the MK-1775 EC50 by 5-fold to an average of 45 nM	23148684
A498	200/2000 nM	Growth Inhibition Assay	24 h	decreases the IC50 of Gemcitabine	24359526
AsPC-1	200/2000 nM	Growth Inhibition Assay	24 h	decreases the IC50 of Gemcitabine	24359526
AsPC-1	10-1000 nM	Growth Inhibition Assay	24-48h	enhances the chemosensitization to gemcitabine	23804422
BxPC-3	10-1000 nM	Growth Inhibition Assay	24-48h	enhances the chemosensitization to gemcitabine	23804422
H1299	500 nM	Growth Inhibition Assay	24 h	enhances the chemosensitization to PMX	24113549
H1437	500 nM	Growth Inhibition Assay	24 h	enhances the chemosensitization to PMX	24113549
H1993	500 nM	Growth Inhibition Assay	24 h	enhances the chemosensitization to PMX	24113549
H2009	500 nM	Cell Viability Assay	72 h	results in G1/S-phase accumulation combined with MK-1775	23148684
H23	500 nM	Growth Inhibition Assay	24 h	enhances the chemosensitization to PMX	24113549
HCC2998	200/2000 nM	Growth Inhibition Assay	24 h	decreases the IC50 of Gemcitabine	24359526
HCT115	200/2000 nM	Growth Inhibition Assay	24 h	decreases the IC50 of Gemcitabine	24359526
HCT116	200/2000 nM	Growth Inhibition Assay	24 h	decreases the IC50 of Gemcitabine	24359526
HCT116	1 µM	Function Assay	24 h	abrogates of cell cycle arrest	22510560
HL-60	30/100/300 nM	Apoptosis Assay	24 h	enhances cytarabine-induced apoptosis	22869869
HMEC	500 nM	Cell Viability Assay	72 h	results in G1/S-phase accumulation combined with MK-1775	23148684
HRE	500 nM	Cell Viability Assay	72 h	results in G1/S-phase accumulation combined with MK-1775	23148684
IGROV-1	200/2000 nM	Growth Inhibition Assay	24 h	decreases the IC50 of Gemcitabine	24359526
MCF10A	200/2000 nM	Growth Inhibition Assay	24 h	decreases the IC50 of Gemcitabine	24359526
MDA-MB-231	200/2000 nM	Growth Inhibition Assay	24 h	decreases the IC50 of Gemcitabine	24359526
MDA-MB-435	200/2000 nM	Growth Inhibition Assay	24 h	decreases the IC50 of Gemcitabine	24359526
MiaPaCa-2	200/2000 nM	Growth Inhibition Assay	24 h	decreases the IC50 of Gemcitabine	24359526
MiaPaCa-2	10-1000 nM	Growth Inhibition Assay	24-48h	enhances the chemosensitization to gemcitabine	23804422
ML-1	25/50/100 nM	Apoptosis Assay	24 h	enhances cytarabine-induced apoptosis	22869869
MOLM-13	100-700 nM	Apoptosis Assay	48 h	induces apoptosis dose dependently	23536721
MV-4-11	100-700 nM	Apoptosis Assay	48 h	induces apoptosis dose dependently	23536721
OVCAR-8	0.3 µM	Growth Inhibition Assay	8 d	sensitizes the cell lines to gemcitabine	23548269
SKOV3	0.3 µM	Growth Inhibition Assay	8 d	sensitizes the cell lines to gemcitabine	23548269
SNB19	200/2000 nM	Growth Inhibition Assay	24 h	decreases the IC50 of Gemcitabine	24359526
Su.86.86	500 nM	Cell Viability Assay	72 h	results in G1/S-phase accumulation combined with MK-1775	23148684
SW620	200/2000 nM	Growth Inhibition Assay	24 h	decreases the IC50 of Gemcitabine	24359526
TK10	200/2000 nM	Growth Inhibition Assay	24 h	decreases the IC50 of Gemcitabine	24359526
U20S	200/2000 nM	Growth Inhibition Assay	24 h	decreases the IC50 of Gemcitabine	24359526
U251	200/2000 nM	Growth Inhibition Assay	24 h	decreases the IC50 of Gemcitabine	24359526
U2OS	2 µM	Function Assay	0-24 h	induces phosphorylation of Chk1 at serine 345 at both concentrations as early as 2 h after administration	22937147
U2OS	0-10 µM	Growth Inhibition Assay	24/48 h	inhibits cell growth dose dependently	22937147
U2OS	1 µM	Function Assay	24 h	abrogates of cell cycle arrest	22510560
U87	200/2000 nM	Growth Inhibition Assay	24 h	decreases the IC50 of Gemcitabine	24359526
U937	100-700 nM	Apoptosis Assay	48 h	induces apoptosis dose dependently	23536721
U937	100-500 nM	Function Assay	4 h	decreases the cytarabine-induced Chk1 autophosphorylation at Ser296 and prevents Cdc25A downregulation	22869869
U937	100 nM	Function Assay	4 h	reverses the cytarabine-induced inhibition of 3H-thymidine incorporation into DNA	22869869
U937	100-500 nM	Function Assay	4 h	induces increased phosphorylation of H2AX	22869869

NCT号	适应症或疾病	临床期	招募状态	预计完成时间	地点

NCT01521299	Advanced Solid Tumors	Phase 1	Withdrawn(Insufficient populat... more >>ion of eligible patients.) Collapse <<	December 2013	-
NCT00907517	Myelogenous Leukemia, Acute ... more >> Leukemia, Lymphocytic, Acute Leukemia, Lymphoblastic, Acute, Philadelphia-Positive Myelogenous Leukemia, Chronic, Aggressive Phase Collapse <<	Phase 1	Terminated	-	-
NCT00907517	-	-	Terminated	-	-
NCT01870596	Adult Acute Megakaryoblastic L... more >>eukemia Adult Acute Monoblastic Leukemia Adult Acute Monocytic Leukemia Adult Acute Myeloid Leukemia With Inv(16)(p13.1q22); CBFB-MYH11 Adult Acute Myeloid Leukemia With Maturation Adult Acute Myeloid Leukemia With Minimal Differentiation Adult Acute Myeloid Leukemia With t(16;16)(p13.1;q22); CBFB-MYH11 Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); RUNX1-RUNX1T1 Adult Acute Myeloid Leukemia With t(9;11)(p22;q23); MLLT3-MLL Adult Acute Myeloid Leukemia Without Maturation Adult Acute Myelomonocytic Leukemia Adult Erythroleukemia Adult Pure Erythroid Leukemia Alkylating Agent-Related Acute Myeloid Leukemia Recurrent Adult Acute Myeloid Leukemia Collapse <<	Phase 2	Completed	-	United States, Arizona ... more >> Mayo Clinic in Arizona Scottsdale, Arizona, United States, 85259 United States, Georgia Blood and Marrow Transplant Group of Georgia Atlanta, Georgia, United States, 30342 United States, Maryland Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Hospital Baltimore, Maryland, United States, 21231 Johns Hopkins University/Sidney Kimmel Comprehensive Cancer Center Baltimore, Maryland, United States, 21287 United States, Minnesota Mayo Clinic Rochester, Minnesota, United States, 55905 Collapse <<
NCT00779584	Hodgkin Disease ... more >> Lymphoma, Non-Hodgkin Neoplasms Collapse <<	Phase 1	Completed	-	-
NCT01870596	-	-	Completed	-	-
NCT00779584	-	-	Completed	-	-

SCH900776 Catalog No. CSN16049

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