MK-8776 (SCH 900776)

Alias: SCH900776; MK8776; SCH-900776; MK-8776; SCH 900776; MK 8776

Cat No.:V1584 Purity: ≥98%

COA Product Data Instructions for use SDS

MK-8776 (SCH 900776) Chemical Structure CAS No.: 891494-63-6
Product category: Chk

This product is for research use only, not for human use. We do not sell to patients.

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1-708-310-1919 sales@invivochem.com

Other Forms of MK-8776 (SCH 900776):

SCH900776 S-isomer (MK-8776 S-isomer)

Official Supplier of:

Top Publications Citing lnvivochem Products

Nature 2021, 597(7874):119-125.

Cell 2020,183:1202-1218.e25.

Science Adv 2022: 8, eabm9427.

Nature 597, 119–125 (2021)

Cell Stem Cell 2020,26(6):845-861.e12.

Science Trans Med 2023,15(701):eadd7872.

STTT 2023,8(1):91.

Cell Reports 2023,42(4):112313

Science Trans Med 2023, 15: eadd7872.

Cancer Cell 2021,39(4):529-547.e7.

Cancer Discov 2022,12(4):1106-1127.

Immunity 2023,56(3):620-634.e11.

J Am Chem Soc 2022,144:21831-21836.

Cell 2020,183:1202-1218.e25.

Science Adv 2022:8,eabm9427.

Nature 2021,597(7874):119-125.

Cell 2020,183:1202-1218.e25.

PNAS Nexus 2022,1(3):pgac063.

ACS Nano 2023,17(10):9110-9125.

Biomaterial 2023 Sep16:302:122333.

Purity & Quality Control Documentation

Current batch：

Purity: ≥98%

COA

MSDS

NMR

Instructions

Product Description
Bioactivity & Protocols
Physicochemical Properties
Solubility Data
Calculators
Clinical Trial Information
Biological Data

Product Description

MK-8776 (also known as SCH900776; MK8776; SCH-900776; MK 8776) is a novel, highly potent and selective Chk1 (cell cycle checkpoint kinase 1) inhibitor with potential antineoplastic, radiosensitization and chemosensitization activities. In a cell-free assay, it inhibits Chk1 with an IC50 of 3 nM. Against Chk2, MK-8776 exhibits 500-fold selectivity. Tumor cells may avoid Chk1-dependent cell cycle arrest in the S and G2/M phases and instead undergo DNA repair before entering mitosis as a result of MK-8776's specific binding to and inhibition of Chk1. This could make tumor cells more vulnerable to the DNA-damaging effects of ionizing radiation and alkylating chemotherapeutic agents.

Biological Activity I Assay Protocols (From Reference)

Targets

Chk1 (IC50 = 3 nM); Chk2 (IC50 = 1500 nM); CDK2 (IC50 = 160 nM)

ln Vitro

SCH 900776 has an IC50 of 0.16 μM and 1.5 μM, respectively, making it a less effective inhibitor of CDK2 and Chk2. Human liver microsomal cytochrome P450 isoforms 1A2, 2C9, 2C19, 2D6, and 3A4 are not significantly inhibited by SCH 900776. Within 24 hours following exposure to hydroxyurea, SCH 900776 causes a dose-dependent reduction in DNA replication capacity. The hydroxyurea, 5-fluoruracil, and cytarabine γ-H2AX response is improved by SCH 900776. Within two hours, when combined with an antimetabolite, SCH 900776 causes an accumulation of γ-H2AX, which is a sign of double stranded DNA breaks and replication fork collapse. Moreover, SCH 900776 dose-dependently inhibits the build-up of Chk1 pS296 autophosphorylation. Chk1 pS345 is rapidly and dose-dependently accumulated when proliferating WS1 cells are exposed to SCH 900776. This suggests that cycling populations of normal cells induce Chk1 pS345 after being exposed to SCH 900776 as part of a futile cycle, which may be fueled by AT-family kinases and DNA-PK.[1]

ln Vivo

When SCH 900776 is administered half an hour after gemcitabine, 4 mg/kg is enough to cause the γ-H2AX biomarker, and 8 mg/kg produces better tumor pharmacodynamic and regression responses than either SCH 900776 or gemcitabine alone. Increases in SCH 900776 dosage (16 mg/kg and 32 mg/kg) cause tumor response to improve gradually. Crucially, in BALB/c mice, doses of SCH 900776 that are linked to strong biomarker activation and better tumor response are not linked to increased gemcitabine toxicity on hematological parameters.[1]

Enzyme Assay

General selectivity data for SCH 900776 against a variety of serine/threonine and tyrosine kinases is produced via the Kinase Profiler service. SCH 900776 is usually used in assays at two concentrations (0.5 and 5 μM) with a fixed (10 μM) concentration of ATP.

Cell Assay

In order to conduct cell growth assays, 500–1000 cells are seeded at a low density into 96-well plates, and the cells are then treated with the drug for a full day (8 wells per concentration). After treatment, cells are rinsed and cultured in new media at 37°C for five to seven days. The cells are lysed, cleaned, and stained with Hoechst 33258 before they reach confluence. Using a microplate spectrofluorometer, fluorescence is measured. The mean and standard error for the drug concentration that 50% inhibited growth are used to express the results.

Animal Protocol

Certain cell lines are grown in vitro, once they have been washed with PBS, they are resuspended in 50% Matrigel in PBS to a final concentration of 4×10⁷ to 5×10⁷ cells per mL for tumor implantation. A subcutaneous injection of 0.1 mL of this suspension is given to naked mice in the flank area. Tumor length (L), width (W), and height (H) are measured twice a week on each mouse using a caliper. The tumor volume is then determined using the formula (L×W×H)/2. Ten animals are randomly assigned to treatment groups and given intraperitoneally either SCH 900776 (formulated in 20% hydroxypropyl β-cyclodextrin) or specific chemotherapeutic agents, prepared in accordance with recommended guidelines. Measurements are taken both during and after the treatment phases of the tumor volumes and body masses. Prior to normalization to starting volume, data are recorded as means±SEM. In some experiments, time to progression to 10x starting volume, or TTP 10x, is recorded. The tumor and surrounding skin are removed during necropsy, preserved for an overnight period in 10% formalin, and then cleaned and preserved in 70% ethanol for pharmacodynamic marker analyses in mice. Shave an area about 4 square inches in size in order to perform skin punch biopsies. In order to induce local anesthesia in dogs, lidocaine is administered subcutaneously, while inhaled isofluorane is used for anesthesia in rats. Using a 4 mm biopsy punch, samples are obtained. Before being cleaned or stored in 70% ethanol, skin punches are fixed in 10% formalin for an entire night.

References

[1]. Mol Cancer Ther . 2011 Apr;10(4):591-602.

[2]. Mol Cancer Ther . 2012 Feb;11(2):427-38.

[3]. Clin Cancer Res . 2012 Oct 1;18(19):5364-73.

[4]. Nat Genet . 2021 Aug;53(8):1207-1220.

These protocols are for reference only. InvivoChem does not independently validate these methods.

Physicochemical Properties

Molecular Formula

C15H18BRN7

Molecular Weight

376.25

Exact Mass

375.08

Elemental Analysis

C, 47.88; H, 4.82; Br, 21.24; N, 26.06

CAS #

891494-63-6

Related CAS #

SCH900776 (S-isomer);891494-64-7

Appearance

white to off-white Solid powder

SMILES

CN1C=C(C=N1)C2=C3N=C(C(=C(N3N=C2)N)Br)[C@@H]4CCCNC4

InChi Key

GMIZZEXBPRLVIV-SECBINFHSA-N

InChi Code

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-/m1/s1

Chemical Name

6-bromo-3-(1-methylpyrazol-4-yl)-5-[(3R)-piperidin-3-yl]pyrazolo[1,5-a]pyrimidin-7-amine

Synonyms

SCH900776; MK8776; SCH-900776; MK-8776; SCH 900776; MK 8776

HS Tariff Code

2934.99.9001

Storage

Powder -20°C 3 years

4°C 2 years

In solvent -80°C 6 months

-20°C 1 month

Shipping Condition

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Solubility Data

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

(Please use freshly prepared in vivo formulations for optimal results.)

Preparing Stock Solutions		1 mg	5 mg	10 mg
	1 mM	2.6578 mL	13.2890 mL	26.5781 mL
	5 mM	0.5316 mL	2.6578 mL	5.3156 mL
	10 mM	0.2658 mL	1.3289 mL	2.6578 mL

*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.

Calculator

Mass

Concentration

Volume

Molecular Weight*

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Molarity Calculator allows you to calculate the mass, volume, and/or concentration required for a solution, as detailed below:

Calculate the Mass of a compound required to prepare a solution of known volume and concentration
Calculate the Volume of solution required to dissolve a compound of known mass to a desired concentration
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See Example

An example of molarity calculation using the molarity calculator is shown below:
What is the mass of compound required to make a 10 mM stock solution in 5 ml of DMSO given that the molecular weight of the compound is 350.26 g/mol?

Enter 350.26 in the Molecular Weight (MW) box
Enter 10 in the Concentration box and choose the correct unit (mM)
Enter 5 in the Volume box and choose the correct unit (mL)
Click the “Calculate” button
The answer of 17.513 mg appears in the Mass box. In a similar way, you may calculate the volume and concentration.

Concentration (Start)

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Concentration (End)

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Dilution Calculator allows you to calculate how to dilute a stock solution of known concentrations. For example, you may Enter C1, C2 & V2 to calculate V1, as detailed below:

What volume of a given 10 mM stock solution is required to make 25 ml of a 25 μM solution?
Using the equation C1V1 = C2V2, where C1=10 mM, C2=25 μM, V2=25 ml and V1 is the unknown:

Enter 10 into the Concentration (Start) box and choose the correct unit (mM)
Enter 25 into the Concentration (End) box and select the correct unit (mM)
Enter 25 into the Volume (End) box and choose the correct unit (mL)
Click the “Calculate” button
The answer of 62.5 μL (0.1 ml) appears in the Volume (Start) box

Molecular formula

Total molecular weight

g/mol

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Molecular Weight Calculator allows you to calculate the molar mass and elemental composition of a compound, as detailed below:

Note: Chemical formula is case sensitive: C12H18N3O4 c12h18n3o4
Instructions to calculate molar mass (molecular weight) of a chemical compound:

To calculate molar mass of a chemical compound, please enter the chemical/molecular formula and click the “Calculate’ button.

Definitions of molecular mass, molecular weight, molar mass and molar weight:

Molecular mass (or molecular weight) is the mass of one molecule of a substance and is expressed in the unified atomic mass units (u). (1 u is equal to 1/12 the mass of one atom of carbon-12)
Molar mass (molar weight) is the mass of one mole of a substance and is expressed in g/mol.

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Reconstitution Calculator allows you to calculate the volume of solvent required to reconstitute your vial.

Enter the mass of the reagent and the desired reconstitution concentration as well as the correct units
Click the “Calculate” button
The answer appears in the Volume (to add to vial) box

In vivo Formulation Calculator (Clear solution)

Step 1: Enter information below (Recommended: An additional animal to make allowance for loss during the experiment)

Dosage mg/kg

Average weight of animals g

Dosing volume per animal μL

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Step 2: Enter in vivo formulation (This is only a calculator, not the exact formulation for a specific product. Please contact us first if there is no in vivo formulation in the solubility section.)

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Calculation results

Working concentration： mg/mL；

Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.

Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH₂O，mix and clarify.

Note： (1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.

Clinical Trial Information

NCT Number	Recruitment	interventions	Conditions	Sponsor/Collaborators	Start Date	Phases
NCT00779584	Completed	Drug: MK-8776 Drug: Gemcitabine	Hodgkin Disease Neoplasms	Merck Sharp & Dohme LLC	October 17, 2008	Phase 1
NCT01870596	Completed	Drug: CHK1 Inhibitor SCH 900776 Drug: Cytarabine	Adult Acute Monocytic Leukemia Adult Erythroleukemia	National Cancer Institute (NCI)	May 2013	Phase 2
NCT00907517	Completed	Drug: MK-8776 Drug: Cytarabine	Myelogenous Leukemia, Acute Leukemia, Lymphocytic, Acute	Merck Sharp & Dohme LLC	July 29, 2009	Phase 1

Biological Data

Comparative efficacy of UCN-01 and SCH900776 at inhibiting Chk1 and abrogating SN38-induced cell cycle arrest.Mol Cancer Ther.2012 Feb;11(2):427-38.
The impact of checkpoint inhibitors on sensitivity of cells to SN38, hydroxyurea and cisplatin.Mol Cancer Ther.2012 Feb;11(2):427-38.
Analysis of cell cycle perturbation induced by hydroxyurea.Mol Cancer Ther.2012 Feb;11(2):427-38.
Impact of concentration and schedule of hydroxyurea and SCH900776 on DNA damage and cytotoxicityA.Mol Cancer Ther.2012 Feb;11(2):427-38.

Comparative efficacy of UCN-01 and SCH900776 at abrogating SN38-induced cell cycle arrest in cells suppressed for Chk1.A.MDA-MB-231ΔChk1 cells were incubated with 10 ng/mL SN38 for 24 h.Mol Cancer Ther.2012 Feb;11(2):427-38.