A8477-5mg | MK-8776 (SCH-900776) [891494-63-6] Clinisciences

SCH 900776 is a potent and selective inhibitor of cell cycle checkpoint kinase 1 (Chk1), Chk2 and Cdk3 with IC50 value of 3 nM, 1.5µM and 0.16 µM, respectively.

Chk is s serine/threonine kinase that senses signal of DNA damage and stalls DNA replication, and also plays an essential role in the maintenance of replication fork viability during exposure to DNA antimetabolites.

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 BALB/c mice, administration of SCH 900776 at a dosage of 8mg/kg after gemcitabine treatment can sufficiently induce enhanced tumor pharmacodynamic and regression responses as compared to gemcitabine or SCH 900776 alone 1.

Reference:
1. Guzi TJ, Paruch K, Dwyer MP, et al. Targeting the replication checkpoint using SCH 900776, a potent and functionally selective CHK1 inhibitor identified via high
content screening. Molecular cancer therapeutics. 2011;10(4):591-602.

1. Molkentine JM, Molkentine DP, et al. "Targeting DNA damage response in head and neck cancers through abrogation of cell cycle checkpoints." Int J Radiat Biol. 2020;1–8. PMID:32073931
2. N. Sanjib Banerjee, Dianne Moore, et al. "Targeting DNA Damage Response as a Strategy to Treat HPV Infections." Int. J. Mol. Sci. 2019, 20(21), 5455.
3. Bourgeois A, Bonnet S, et al. "Inhibition of CHK 1 (Checkpoint Kinase 1) Elicits Therapeutic Effects in Pulmonary Arterial Hypertension." Arterioscler Thromb Vasc Biol. 2019 Aug;39(8):1667-1681. PMID:31092016

Storage	Store at -20°C
M.Wt	376.25
Cas No.	891494-63-6
Formula	C₁₅H₁₈BrN₇
Solubility	insoluble in H2O; insoluble in EtOH; ≥18.8 mg/mL in DMSO
Chemical Name	(R)-6-bromo-3-(1-methyl-1H-pyrazol-4-yl)-5-(piperidin-3-yl)pyrazolo[1,5-a]pyrimidin-7-amine
SDF	Download SDF
Canonical SMILES	BrC(C([C@@H]1CCCNC1)=N2)=C(N)N3C2=C(C4=CN(C)N=C4)C=N3
Shipping Condition	Small Molecules with Blue Ice, Modified Nucleotides with Dry Ice.
General tips	We do not recommend long-term storage for the solution, please use it up soon.

Cell experiment [1]:
Cell lines	U2OS cells
Preparation method	The solubility of this compound in DMSO is >18.8mg/mL. General tips for obtaining a higher concentration: Please warm the tube at 37℃ for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below -20℃ for several months.
Reacting condition	2h
Applications	In U2OS cells, SCH 900776 induced a dose-dependent loss of DNA replication capability 24 hours after hydroxyurea exposure. SCH 900776 enhanced apoptosis for at least 48 hours following release from hydroxyurea blockade.
Animal experiment [1]:
Animal models	BALB/c mice bearing A2780 xenografts
Dosage form	4-32 mg/kg
Application	SCH-900776 (8 mg/kg) led to enhanced tumor pharmacodynamic and regression responses. SCH 900776 (16 and 32 mg/kg) induced incremental improvements in tumor response.
Other notes	Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal.
References: [1] Guzi T J, Paruch K, Dwyer M P, et al. Targeting the replication checkpoint using SCH 900776, a potent and functionally selective CHK1 inhibitor identified via high content screening[J]. Molecular cancer therapeutics, 2011, 10(4): 591-602.