MK-8776 S-isomer

MK-8776 S-isomer is the S-isomer of SCH900776. SCH900776 is a potent, selective and orally bioavailable inhibitor of checkpoint kinase1 (Chk1) with IC50 of 3 nM.

Product information

CAS Number: 891494-64-7

Molecular Weight: 376.25

Formula: C15H18BrN7

Synonym:

SCH900776 S-isomer

Chemical Name: MK-8776 S-isomer

Smiles: CN1C=C(C=N1)C1C=NN2C(N)=C(Br)C(=NC2=1)[C@@H]1CNCCC1

InChiKey: GMIZZEXBPRLVIV-VIFPVBQESA-N

InChi: InChI=1S/C15H18BrN7/c1-22-8-10(6-19-22)11-7-20-23-14(17)12(16)13(21-15(11)23)9-3-2-4-18-5-9/h6-9,18H,2-5,17H2,1H3/t9-/m0/s1

Technical Data

Appearance: Solid Power

Purity: ≥98% (or refer to the Certificate of Analysis)

Solubility: ≥ 37.6 mg/mL in DMSO, ≥ 47.8 mg/mL in EtOH with ultrasonic

Shipping Condition: Shipped under ambient temperature as non-hazardous chemical or refer to Certificate of Analysis

Storage Condition: Dry, dark and -20 ^oC for 1 year or refer to the Certificate of Analysis.

Shelf Life: ≥12 months if stored properly.

Stock Solution Storage: 0 - 4 ^oC for 1 month or refer to the Certificate of Analysis.

Drug Formulation: To be determined.

HS Tariff Code: 382200

How to use

In Vitro:

MK-8776 S-isomer is a less potent inhibitor of Chk2 and CDK2 with IC50 of 1.5 μM and 0.16 μM, respectively. MK-8776 S-isomer shows no significant inhibition of cytochrome P450 human liver microsomal isoforms 1A2, 2C9, 2C19, 2D6, and 3A4. MK-8776 S-isomer induces a dose-dependent loss of DNA replication capability 24 hours after hydroxyurea exposure. MK-8776 S-isomer enhances the γ-H2AX response of hydroxyurea, 5-fluoruracil, and cytarabine. In combination with an antimetabolite, MK-8776 S-isomer induces accumulation of γ-H2AX within 2 hours, indicative of replication fork collapse and double stranded DNA breaks. Additionally, MK-8776 S-isomer suppresses accumulation of the Chk1 pS296 autophosphorylation in a dose-dependent manner. Exposure of proliferating WS1 cells to MK-8776 S-isomer is associated with rapid, dose-dependent accumulation of Chk1 pS345, indicating that cycling populations of normal cells induce Chk1 pS345 following exposure to MK-8776 S-isomer 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 MK-8776 S-isomer is sufficient to induce the γ-H2AX biomarker while 8 mg/kg leads to enhanced tumor pharmacodynamic and regression responses relative to gemcitabine or MK-8776 S-isomer alone. Dose escalation of MK-8776 S-isomer (16 mg/kg and 32 mg/kg) induces incremental improvements in tumor response. Importantly, doses of MK-8776 S-isomer associate with robust biomarker activation and improved tumor response are not associated with enhanced toxicity of gemcitabine on hematological parameters in BALB/c mice.

References:

1. Guzi TJ, et al. Mol Y Ther, 2011, 10(4), 591-602.
2. Montano R, et al. Mol Y Ther. 2012 Feb;11(2):427-38.
3. Thompson R, et al. PLoS One. 2012;7(8):e44021.

Products are for research use only. Not for human use.