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MK-8776

(CAS No:891494-63-6)

MK-8776 (SCH 900776) is a selective Chk1 inhibitor with IC50 of 3 nM in a cell-free assay. It shows 500-fold selectivity against Chk2. Phase 2.

CAS No:891494-63-6

Molecular Weight(MW):376.25

Purity:99.00%

Specification:500MG;1G;5G;10G;50G;100G

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QC Documents

COA	MSDS	HPLC	NMR

ChemicalInfomation

CAS No:	891494-63-6
Molecular formula(MF)	C₁₅H₁₈BrN₇
Molecular Weight(MW):	376.25
Alias

Solubility

In vitro	DMSO	3 mg/mL (7.97 mM)
	Water	<1 mg/mL
	Ethanol	<1 mg/mL
In vivo	4% DMSO+30% propylene glycol	5 mg/mL

Biological Activity

Description

MK-8776 (SCH 900776) is a selective Chk1 inhibitor with IC50 of 3 nM in a cell-free assay. It shows 500-fold selectivity against Chk2. Phase 2.

Targets

Chk1 ^[1] (Cell-free assay)	CDK2 ^[1] (Cell-free assay)	Chk2 ^[1] (Cell-free assay)
3 nM	0.16 μM	1.5 μM

In vitro

SCH 900776 is a less potent inhibitor of Chk2 and CDK2 with IC50 of 1.5 μM and 0.16 μM, respectively. SCH 900776 shows no significant inhibition of cytochrome P450 human liver microsomal isoforms 1A2, 2C9, 2C19, 2D6, and 3A4. SCH 900776 induces a dose-dependent loss of DNA replication capability 24 hours after hydroxyurea exposure. SCH 900776 enhances the γ-H2AX response of hydroxyurea, 5-fluoruracil, and cytarabine. In combination with an antimetabolite, SCH 900776 induces accumulation of γ-H2AX within 2 hours, indicative of replication fork collapse and double stranded DNA breaks. Additionally, SCH 900776 suppresses accumulation of the Chk1 pS296 autophosphorylation in a dose-dependent manner. Exposure of proliferating WS1 cells to SCH 900776 is associated with rapid, dose-dependent accumulation of Chk1 pS345, indicating that cycling populations of normal cells induce Chk1 pS345 following exposure to SCH 900776 as part of a futile cycle, perhaps driven by AT-family kinases and DNA-PK.^[1]

Cell Data

Cell Lines	Assay Type	Concentration	Incubation Time	Formulation	Activity Description	PMID
U251	Growth Inhibition Assay	200/2000 nM	24 h		decreases the IC50 of Gemcitabine	24359526
HCT115	Growth Inhibition Assay	200/2000 nM	24 h		decreases the IC50 of Gemcitabine	24359526
SW620	Growth Inhibition Assay	200/2000 nM	24 h		decreases the IC50 of Gemcitabine	24359526
IGROV-1	Growth Inhibition Assay	200/2000 nM	24 h		decreases the IC50 of Gemcitabine	24359526
HCT116	Growth Inhibition Assay	200/2000 nM	24 h		decreases the IC50 of Gemcitabine	24359526
MCF10A	Growth Inhibition Assay	200/2000 nM	24 h		decreases the IC50 of Gemcitabine	24359526
MiaPaCa-2	Growth Inhibition Assay	200/2000 nM	24 h		decreases the IC50 of Gemcitabine	24359526
MDA-MB-231	Growth Inhibition Assay	200/2000 nM	24 h		decreases the IC50 of Gemcitabine	24359526
HCC2998	Growth Inhibition Assay	200/2000 nM	24 h		decreases the IC50 of Gemcitabine	24359526
U87	Growth Inhibition Assay	200/2000 nM	24 h		decreases the IC50 of Gemcitabine	24359526
MDA-MB-435	Growth Inhibition Assay	200/2000 nM	24 h		decreases the IC50 of Gemcitabine	24359526
SNB19	Growth Inhibition Assay	200/2000 nM	24 h		decreases the IC50 of Gemcitabine	24359526
U20S	Growth Inhibition Assay	200/2000 nM	24 h		decreases the IC50 of Gemcitabine	24359526
A498	Growth Inhibition Assay	200/2000 nM	24 h		decreases the IC50 of Gemcitabine	24359526
TK10	Growth Inhibition Assay	200/2000 nM	24 h		decreases the IC50 of Gemcitabine	24359526
AsPC-1	Growth Inhibition Assay	200/2000 nM	24 h		decreases the IC50 of Gemcitabine	24359526
H23	Growth Inhibition Assay	500 nM	24 h	DMSO	enhances the chemosensitization to PMX	24113549
H1437	Growth Inhibition Assay	500 nM	24 h	DMSO	enhances the chemosensitization to PMX	24113549
H1993	Growth Inhibition Assay	500 nM	24 h	DMSO	enhances the chemosensitization to PMX	24113549
H1299	Growth Inhibition Assay	500 nM	24 h	DMSO	enhances the chemosensitization to PMX	24113549
AsPC-1	Growth Inhibition Assay	10-1000 nM	24-48h		enhances the chemosensitization to gemcitabine	23804422
MiaPaCa-2	Growth Inhibition Assay	10-1000 nM	24-48h		enhances the chemosensitization to gemcitabine	23804422
BxPC-3	Growth Inhibition Assay	10-1000 nM	24-48h		enhances the chemosensitization to gemcitabine	23804422
SKOV3	Growth Inhibition Assay	0.3 ÂµM	8 d		sensitizes the cell lines to gemcitabineÂ	23548269
OVCAR-8	Growth Inhibition Assay	0.3 ÂµM	8 d		sensitizes the cell lines to gemcitabineÂ	23548269
MV-4-11	Apoptosis Assay	100-700 nM	48 h		induces apoptosis dose dependently	23536721
U937	Apoptosis Assay	100-700 nM	48 h		induces apoptosis dose dependently	23536721
MOLM-13	Apoptosis Assay	100-700 nM	48 h		induces apoptosis dose dependently	23536721
A2058	Cell Viability Assay	37.5-300 nM	72 h	DMSO	reduces the MK-1775 EC50Â by 5-fold to an average of 45 nM	23148684
H2009	Cell Viability Assay	500 nM	72 h	DMSO	results in G1/S-phase accumulation combined with MK-1775	23148684
Su.86.86	Cell Viability Assay	500 nM	72 h	DMSO	results in G1/S-phase accumulation combined with MK-1775	23148684
HRE	Cell Viability Assay	500 nM	72 h	DMSO	results in G1/S-phase accumulation combined with MK-1775	23148684
HMEC	Cell Viability Assay	500 nM	72 h	DMSO	results in G1/S-phase accumulation combined with MK-1775	23148684
U2OS	Function Assay	2 ÂµM	0-24 h		induces phosphorylation of Chk1 at serine 345 at both concentrations as early as 2 h after administration	22937147
U2OS	Growth Inhibition Assay	0-10 ÂµM	24/48 h		inhibits cell growth dose dependently	22937147
U937	Function Assay	100-500 nM	4 hÂ		decreases the cytarabine-induced Chk1 autophosphorylation at Ser296Â and prevents Cdc25A downregulation	22869869
U937	Function Assay	100 nM	4 hÂ		reverses the cytarabine-induced inhibition ofÂ 3H-thymidine incorporation into DNA	22869869
U937	Function Assay	100-500 nM	4 hÂ		induces increased phosphorylation of H2AX	22869869
HL-60	Apoptosis Assay	30/100/300 nM	24 h	DMSO	enhances cytarabine-induced apoptosis	22869869
ML-1	Apoptosis Assay	25/50/100 nM	24 h	DMSO	enhances cytarabine-induced apoptosis	22869869
HCT116	Function Assay	1 ÂµM	24 h		abrogates of cell cycle arrestÂ	22510560
U2OS	Function Assay	1 ÂµM	24 h		abrogates of cell cycle arrestÂ	22510560

... Click to View More Cell Line Experimental Data

In vivo

Administered 30 minutes after gemcitabine, 4 mg/kg SCH 900776 is sufficient to induce the γ-H2AX biomarker while 8 mg/kg leads to enhanced tumor pharmacodynamic and regression responses relative to gemcitabine or SCH 900776 alone. Dose escalation of SCH 900776 (16 mg/kg and 32 mg/kg) induces incremental improvements in tumor response. Importantly, doses of SCH 900776 associate with robust biomarker activation and improved tumor response are not associated with enhanced toxicity of gemcitabine on hematological parameters in BALB/c mice. ^[1]