product name MK-8776 (SCH 900776)
Description: MK-8776 (also known as SCH 900776) is a highly potent and selective Chk1 inhibitor with IC50 of 3 nM in a cell-free assay. It shows 500-fold selectivity against Chk2. SCH900776, MK-8776 is an agent with potential radiosensitization and chemosensitization activities. MK-8776 specifically binds to and inhibits Chk1, which may result in tumor cells bypassing Chk1-dependent cell cycle arrest in the S and G2/M phases to undergo DNA repair prior to entry into mitosis; tumor cells may thus be sensitized to the DNA-damaging effects of ionizing radiation and alkylating chemotherapeutic agents.
References: Mol Cancer Ther. 2011 Apr;10(4):591-602.
376.25
Formula
C15H18BrN7
CAS No.
891494-63-6
Storage
-20℃ for 3 years in powder form
-80℃ for 2 years in solvent
Solubility (In vitro)
DMSO: 3 mg/mL (8.0 mM)
Water: <1 mg/mL
Ethanol: <1 mg/mL
Solubility (In vivo)
4% DMSO+30% Propylene glycol: 5 mg/mL
Synonyms
SCH900776
other peoduct :References PubMed ID：:http://www.ncbi.nlm.nih.gov/pubmed/19406331
| In Vitro |
In vitro activity: 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. Kinase Assay: Cell Assay: In vitro, SCH 900776 blocked accumulation of the Chk1 pS296 autophosphorylation in a dose-dependent manner. Treatment of proliferating WS1 cells with SCH 900776 was found to be associated with rapid, dose-dependent accumulation of Chk1 pS345, indicating that cycling populations of normal cells induce Chk1 pS345 in response to the inhibition of SCH 900776 as part of a futile cycle 1. |
|---|---|
| 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. |
| Animal model | Female nude mice injected subcutaneously with A2780 or MiaPaCa2 cells |
| Formulation & Dosage | Formulated in 20% hydroxypropyl β-cyclodextrin; 50 mg/kg; i.p. injection |
| References | Mol Cancer Ther. 2011 Apr;10(4):591-602. |
