AZD7762

Catalog No.S1532 Batch:S153205

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Technical Data

Formula

C17H19FN4O2S
Molecular Weight 362.42 CAS No. 860352-01-8
Solubility (25°C)* In vitro DMSO 72 mg/mL (198.66 mM)
Water Insoluble
Ethanol Insoluble
* <1 mg/ml means slightly soluble or insoluble.
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.
* Room temperature shipping (Stability testing shows this product can be shipped without any cooling measures.)

Preparing Stock Solutions

Biological Activity

Description AZD7762 is a potent and selective inhibitor of Chk1 with IC50 of 5 nM in a cell-free assay. It is equally potent against Chk2 and less potent against CAM, Yes, Fyn, Lyn, Hck and Lck. Phase 1.
Targets
Chk1 [1]
(Cell-free assay)		 Chk2 [1]
(Cell-free assay)
5 nM <10 nM
In vitro AZD7762, a more selective Chk1 inhibitor, inhibits Chk1 phosphorylation of a cdc25C peptide by reversibly binding to the ATP-binding site of Chk1, with IC50 of 5 nM and Ki of 3.6 nM. AZD7762 induces cell arrest with EC50 of 0.620 μM, and significantly abrogates the camptothecin induced G2 arrest with an EC50 of 10 nM, by blocking the chk1 dependent degradation of Cdc25A and activation of Cyclin A. AZD7762 (300 nM) enhances the antitumor efficacy of gemcitabine against SW620 and topotecan against MDA-MB-231 by reducing the GI50 values from 24.1 nM and 2.25 μM to 1.08 nM and 0.15 μM, respectively. [1] AZD7762 shows cytotoxicity against a variety of neuroblastoma cell lines bearing p53 wild type, p53 mutation, Mdm2 amplification or p14 deletion with IC50 values ranging from 82.6-505.9 nM. [2]
In vivo AZD7762 alone at 25 mg/kg shows little antitumor activity in the H460-DNp53 xenograft mice and SW620 xenograft mice, but when administrated in combination with gemcitabine (60 mg/kg), AZD7762 shows significant antitumor efficacy in the two xenografts mice with a log cell kill of 0.9 or percent treated/control (%T/C) of 26 even at low dose of 12.5 mg. Dosing of AZD7762 in combination with gemcitabine (10 mg/kg) in the H460-DNp53 xenograft rat inhibits the tumor volume in a dose-dependent manner with the %T/C values of 48 and 32 for 10 and 20 mg/kg AZD7762, respectively. AZD7762 (25 mg/kg) in combination with irinotecan (25 or 50 mg/kg) causes complete tumor regression in the SW620 xenograft mice with the %T/C increasing significantly to -66% and -67%, respectively. [1]

Protocol (from reference)

Kinase Assay:[1]
  • Chk1 Kinase Assay

    Recombinant human Chk1 is expressed as a glutathione S-transferase fusion in insect cells using a baculovirus vector and purified by glutathione affinity chromatography. A synthetic peptide substrate (N-biotinylaminohexanoyl-KKVSRSGLYRSPMPENLNRPR) for Chk1 is synthesized. Final assay concentrations of peptide and ATP (cold + 40 nCi [33P]ATP) are 0.8 and 1 μM, respectively. Different concentrations of AZD7762, buffer containing peptide and chk1 kinase and ATP, are added sequentially to a 384-well assay plate. The plate is incubated for 2 hours, reaction is stopped by the addition of buffer containing EDTA and scintillation proximity assay beads, and plates are read using a TopCount reader. Data analysis is carried out to determinate a dose response (IC50).
Cell Assay:[1]
  • Cell lines

    HT29, SW620 and MDA-MB-231 cells

  • Concentrations

    Dissolved in DMSO, final concentration ~12.5 μM

  • Incubation Time

    20 or 48 hours

  • Method

    For the checkpoint abrogation assay, HT29 cells are treated for 2 hours with camptothecin (topoisomerase I inhibitor; 0.07 μg/mL) to induce the G2 checkpoint. Cells are then treated for 20 hours with a 12-point titration of AZD7762 (12.5 μM to 6 nM) plus nocodazole. Cells are fixed with 3.7% formaldehyde for 1 hour, permeabilized with PBS containing 0.05% Triton X, and incubated with anti-phH3 antibody for 1 hour followed by Alexa Fluor 488 anti-rabbit and Hoechst stain for 1 hour. Mitotic index is determined on the ArrayScan and expressed as the percentage of cells undergoing mitosis. For the potentiation assays, SW620 or MDA-MB-231 cells are dosed for 24 hours with a 9-point titration of gemcitabine ranging from 0.01 to 100 nM with a constant dose of AZD7762 (300 nM). After 24 hours, medium is removed and AZD7762 alone is added back to the wells for an additional 24 hours. Cells are then incubated in AZD7762-free medium for an additional 72 hours. The effect on cell proliferation is determined by MTT.
Animal Study:[1]
  • Animal Models

    Male NCr mice implanted s.c. with H460-DNp53 cells or SW620, and male rnu rats implanted s.c. with H460-DNp53 cells

  • Dosages

    ~25 mg/kg

  • Administration

    Injection i.v.

Customer Product Validation

Data from [Cancer Discov, 2012, 2, 524-39]

Data from [Cancer Biol Ther, 2012, 13]

Data from [Cancer Biol Ther, 2012, 13]

Data from [Cancer Biol Ther, 2011, 12, 215-28]

Selleck's AZD7762 has been cited by 124 publications

Natural pentacyclic triterpenoid from Pristimerin sensitizes p53-deficient tumor to PARP inhibitor by ubiquitination of Chk1 [ Pharmacol Res, 2024, 201:107091] PubMed: 38316371
Multiplexed kinase interactome profiling quantifies cellular network activity and plasticity [ Mol Cell, 2023, 83(5):803-818.e8] PubMed: 36736316
Actionable loss of SLF2 drives B-cell lymphomagenesis and impairs the DNA damage response [ EMBO Mol Med, 2023, e16431.] PubMed: 37485814
BRD7 suppresses tumor chemosensitivity to CHK1 inhibitors by inhibiting USP1-mediated deubiquitination of CHK1 [ Cell Death Discov, 2023, 9(1):313] PubMed: 37626049
Selective ATM inhibition augments radiation-induced inflammatory signaling and cancer cell death [ Aging (Albany NY), 2023, 15(2):492-512] PubMed: 36656721
Cyclin A-CDK1 suppresses the expression of the CDK1 activator CDC25A to safeguard timely mitotic entry [ J Biol Chem, 2023, S0021-9258(23)00089-3] PubMed: 36717077
CHEK2 signaling is the key regulator of oocyte survival after chemotherapy [ Sci Adv, 2023, 9(42):eadg0898] PubMed: 37862420
Replication stress impairs chromosome segregation and preimplantation development in human embryos [ Cell, 2022, 185(16):2988-3007.e20] PubMed: 35858625
Targeting the Retinoblastoma/E2F repressive complex by CDK4/6 inhibitors amplifies oncolytic potency of an oncolytic adenovirus [ Nat Commun, 2022, 13(1):4689] PubMed: 35948546
Development of a nanoparticle-based immunotherapy targeting PD-L1 and PLK1 for lung cancer treatment [ Nat Commun, 2022, 13(1):4261] PubMed: 35871223

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SHIPPING AND STORAGE
Selleck products are transported at room temperature. If you receive the product at room temperature, please rest assured, the Selleck Quality Inspection Department has conducted experiments to verify that the normal temperature placement of one month will not affect the biological activity of powder products. After collecting, please store the product according to the requirements described in the datasheet. Most Selleck products are stable under the recommended conditions.

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