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Datasheet of MK-8776

Description:
SCH900776 is a potent, selective and orally bioavailable inhibitor of checkpoint kinase Chk1 (IC50 = 3 nM), highly selective
against Chk2 (IC50 = 1500 nM) and cyclin-dependent kinase CDK2 (IC50 = 160 nM).
in vitro: SCH 900776 is a less potent inhibitor of Chk2 and CDK2 with IC50 of 1.5 M and 0.16 M, 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 -H2AX response of hydroxyurea, 5-fluoruracil, and cytarabine. In combination with an antimetabolite, SCH
900776 induces accumulation of -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.
in vivo: Administered 30 minutes after gemcitabine, 4 mg/kg SCH 900776 is sufficient to induce the -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.
SCH900776 exposure phenocopies short interfering RNA-mediated CHK1 ablation and interacts synergistically with DNA
antimetabolite agents in vitro and in vivo to selectively induce dsDNA breaks and cell death in tumor cell backgrounds. Chk1
inhibitor SCH 900776 abrogates cytarabine-induced S-phase arrest and enhances cytarabine cytotoxicity in acute leukemia cell
lines and leukemic blasts in vitro.

Chemical Information
Catalog

DC5024

Purity of current batch:

>98%

Molecular Weight (MW)

376.25

Molecular Formula

C15H18BrN7

CAS No.

891494-63-6

Solubility (25C)

DMSO

Storage

Store at -20C (desiccating conditions).

Handling:
Providing storage is as stated on the product vial and the vial is kept tightly sealed, the product can be stored for up to 24 months.
Wherever possible, you should prepare and use solutions on the same day. However, if you need to make up stock solutions in
advance, we recommend that you store the solution as aliquots in tightly sealed vials at -20C. Generally, these will be useable
for up to one month. Before use, and prior to opening the vial we recommend that you allow your product to equilibrate to room
temperature for at least 1 hour.