AZD7762

Checkpoint kinase inhibitor,ATP competitive CAS# 860352-01-8

AZD7762

Catalog No. BCC2555----Order now to get a substantial discount!

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Chemical structure

AZD7762

3D structure

Chemical Properties of AZD7762

Cas No. 860352-01-8 SDF Download SDF
PubChem ID 11152667 Appearance Powder
Formula C17H19FN4O2S M.Wt 362.42
Type of Compound N/A Storage Desiccate at -20°C
Solubility DMSO : 100 mg/mL (275.92 mM; Need ultrasonic)
Chemical Name 3-(carbamoylamino)-5-(3-fluorophenyl)-N-[(3S)-piperidin-3-yl]thiophene-2-carboxamide
SMILES C1CC(CNC1)NC(=O)C2=C(C=C(S2)C3=CC(=CC=C3)F)NC(=O)N
Standard InChIKey IAYGCINLNONXHY-LBPRGKRZSA-N
Standard InChI InChI=1S/C17H19FN4O2S/c18-11-4-1-3-10(7-11)14-8-13(22-17(19)24)15(25-14)16(23)21-12-5-2-6-20-9-12/h1,3-4,7-8,12,20H,2,5-6,9H2,(H,21,23)(H3,19,22,24)/t12-/m0/s1
General tips For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months.
We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months.
Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it.
About Packaging 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial.
2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial.
3. Try to avoid loss or contamination during the experiment.
Shipping Condition Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request.

Biological Activity of AZD7762

DescriptionAZD7762 is a potent and selective inhibitor of Chk1 with IC50 of 5 nM.
TargetsCHK1CHK2    
IC505 nM<10 nM    

Protocol

Cell experiment: [1]

Cell lines

T47D and MCF7 cells

Preparation method

The solubility of this compound in DMSO is >10 mM. General tips for obtaining a higher concentration: Please warm the tube at 37 °C for 10 minutes and/or shake it in the ultrasonic bath for a while.Stock solution can be stored below -20°C for several months.

Reacting condition

100 nM, 24 hours

Applications

A clearly enhanced radiosensitization of AZD7762 was observed in the p53 mutant T47D cells but not in the wild-type p53 MCF7 cells. In the p53 mutant T47D cells, the cytotoxicity produced by AZD7762 in combination with radiation was significantly greater than that caused by the radiation alone. In the wild-type p53 MCF7 cells, although there was a trend for AZD7762 to sensitize cells to radiation, this difference did not reach a statistical significance.

Animal experiment: [2]

Animal models

Female athymic nude mice injected with HT-29 cells

Dosage form

Intraperitoneal injection, 25 mg/kg, given immediately after radiation treatment and 8 hours later

Application

AZD7762 treatment alone had little effect on tumor growth, whereas fractionated radiation delayed tumor growth. The time for tumors to reach thrice the initially measured tumor volume relative to the control for AZD7762 alone, fractionated radiation, and AZD7762 plus fractionated radiation was 2.3 (P < 0.53), 7.4 (P < 0.07), and 18.7 (P < 0.00014) days, respectively. Relative to fractionated radiation alone, the combination of AZD7762 and fractionated radiation was also highly significant. Thus, the combination of AZD7762 and fractionated radiation showed a greater tumor growth delay than the sum of the individual treatments alone.

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] Ma Z, Yao G, Zhou B, et al. The Chk1 inhibitor AZD7762 sensitises p53 mutant breast cancer cells to radiation in vitro and in vivo. Molecular medicine reports, 2012, 6(4): 897-903.

[2] Mitchell J B, Choudhuri R, Fabre K, et al. In vitro and in vivo radiation sensitization of human tumor cells by a novel checkpoint kinase inhibitor, AZD7762. Clinical Cancer Research, 2010, 16(7): 2076-2084.

AZD7762 Dilution Calculator

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AZD7762 Molarity Calculator

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Preparing Stock Solutions of AZD7762

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 2.7592 mL 13.7961 mL 27.5923 mL 55.1846 mL 68.9807 mL
5 mM 0.5518 mL 2.7592 mL 5.5185 mL 11.0369 mL 13.7961 mL
10 mM 0.2759 mL 1.3796 mL 2.7592 mL 5.5185 mL 6.8981 mL
50 mM 0.0552 mL 0.2759 mL 0.5518 mL 1.1037 mL 1.3796 mL
100 mM 0.0276 mL 0.138 mL 0.2759 mL 0.5518 mL 0.6898 mL
* Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations.

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Background on AZD7762

AZD7762 is a novel ATP competitive inhibitor of checkpoint kinases. Chk family checkpoint kinases include Chk1 and Chk2. They are activated in response to DNA damage and phosphorylate CDC25A, CDC25C protein phosphatases, which delay cell cycle progression. Therefore, Chk activation initiates cell cycle checkpoint, causes cell cycle arrest, and allows DNA repair.

AZD7762 is a potent selective inhibitor of Chk1. It binds to the ATP binding pocket and compete ATP binding in a reversible manner. AZD7762 inhibits Chk1 phosphorylation of CDC25C peptide with an IC50 of 5 nM. The Ki is 3.6 nM. It is equally potent against Chk2 but less potent against CAM, Yes, Fyn, Lyn, Hck and Lck. [1]

AZD7762 prevents cell cycle arrest and DNA repair in DNA damaged tumor cells, causing tumor cell apoptosis. Hence, it potentiates the antitumor activity of DNA damaging agents and can be used as a chemosensitizing agent. [2]

Half life of AZD7762 is 1-2 hours in mice [3]

References:
[1]Zabludoff SD, et al. AZD7762, a novel checkpoint kinase inhibitor, drives checkpoint abrogation and potentiates DNA-targeted therapies. Mol Cancer Ther, 2008, 7(9): 2955-2966.
[2]Landau HJ, et al. The checkpoint kinase inhibitor AZD7762 potentiates chemotherapy-induced apoptosis of p53-mutated multiple myeloma cells. Mol Cancer Ther. 2012, 11(8): 1781-1788
[3]Goteti K, et al. Preclinical pharmacokinetic/pharmacodynamic models to predict synergistic effects of co-administered anti-cancer agents. Cancer Chemother Pharmacol. 2010, 66(2): 245-254.

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References on AZD7762

Birinapant (TL32711) Improves Responses to GEM/AZD7762 Combination Therapy in Triple-negative Breast Cancer Cell Lines.[Pubmed:27272773]

Anticancer Res. 2016 Jun;36(6):2649-57.

BACKGROUND: Triple-negative breast cancer (TNBC) is an aggressive form of breast cancer currently lacking targeted therapies. Our previous work demonstrated a therapeutic synergism with gemcitabine (GEM) and the CHK1 inhibitor (AZD7762) combination treatment in a TNBC cell line. We hypothesized that the response to this combination therapy would differ among heterogeneous TNBC patients and that addition of a SMAC mimetic (TL32711) could improve efficacy. MATERIALS AND METHODS: Therapeutic responses to GEM, GEM/AZD7762, and GEM/AZD7762/TL32711 combinations were investigated by XTT assays and western blotting of cell cycle and apoptosis-related proteins in ten TNBC cell lines. RESULTS: TNBC cell lines harboring low levels of endogenous CHK1, cIAP1 and cIAP2 were responsive to GEM alone, whereas cell lines demonstrating a minimal increase in phospho-S345 CHK1 after treatment were responsive to GEM/AZD7762 or GEM/AZD7762/TL32711 combination. CONCLUSION: The response of TNBC cells to particular therapies varies and will require development of predictive biomarkers.

Suppression of the metastatic spread of breast cancer by DN10764 (AZD7762)-mediated inhibition of AXL signaling.[Pubmed:27829217]

Oncotarget. 2016 Dec 13;7(50):83308-83318.

Breast cancer is the most common malignant disease occurring in women and represents a substantial proportion of the global cancer burden. In these patients, metastasis but not the primary tumor is the main cause of breast cancer-related deaths. Here, we report the novel finding that DN10764 (AZD7762, a selective inhibitor of checkpoint kinases 1 and 2) can suppress breast cancer metastasis. In breast cancer cells, DN10764 inhibited cell proliferation and GAS6-mediated AXL signaling, consequently resulting in suppressed migration and invasion. In addition, DN10764 induced caspase 3/7-mediated apoptosis in breast cancer cells and inhibited tube formation of human umbilical vein endothelial cells. Finally, DN10764 significantly suppressed the tumor growth and metastasis of breast cancer cells in in vivo metastasis models. Taken together, these data suggest that therapeutic strategies targeting AXL in combination with systemic therapies could improve responses to anti-cancer therapies and reduce breast cancer recurrence and metastases.

Phase I dose-escalation study of AZD7762, a checkpoint kinase inhibitor, in combination with gemcitabine in US patients with advanced solid tumors.[Pubmed:24448638]

Cancer Chemother Pharmacol. 2014 Mar;73(3):539-49.

PURPOSE: AZD7762 is a Chk1 kinase inhibitor which increases sensitivity to DNA-damaging agents, including gemcitabine. We evaluated the safety of AZD7762 monotherapy and with gemcitabine in advanced solid tumor patients. EXPERIMENTAL DESIGN: In this Phase I study, patients received intravenous AZD7762 on days 1 and 8 of a 14-day run-in cycle (cycle 0; AZD7762 monotherapy), followed by AZD7762 plus gemcitabine 750-1,000 mg/m(2) on days 1 and 8, every 21 days, in ascending AZD7762 doses (cycle 1; combination therapy). RESULTS: Forty-two patients received AZD7762 6 mg (n = 9), 9 mg (n = 3), 14 mg (n = 6), 21 mg (n = 3), 30 mg (n = 7), 32 mg (n = 6), and 40 mg (n = 8), in combination with gemcitabine. Common adverse events (AEs) were fatigue [41 % (17/42) patients], neutropenia/leukopenia [36 % (15/42) patients], anemia/Hb decrease [29 % (12/42) patients] and nausea, pyrexia and alanine aminotransferase/aspartate aminotransferase increase [26 % (11/42) patients each]. Grade >/=3 AEs occurred in 19 and 52 % of patients in cycles 0 and 1, respectively. Cardiac dose-limiting toxicities occurred in two patients (both AZD7762 monotherapy): grade 3 troponin I increase (32 mg) and grade 3 myocardial ischemia with chest pain, electrocardiogram changes, decreased left ventricular ejection fraction, and increased troponin I (40 mg). AZD7762 exposure increased linearly. Gemcitabine did not affect AZD7762 pharmacokinetics. Two non-small-cell lung cancer patients achieved partial tumor responses (AZD7762 6 mg/gemcitabine 750 mg/m(2) and AZD7762 9 mg cohort). CONCLUSIONS: The maximum-tolerated dose of AZD7762 in combination with gemcitabine 1,000 mg/m(2) was 30 mg. Although development of AZD7762 is not going forward owing to unpredictable cardiac toxicity, Chk1 remains an important therapeutic target.

Checkpoint kinase inhibitor AZD7762 strongly sensitises urothelial carcinoma cells to gemcitabine.[Pubmed:28049532]

J Exp Clin Cancer Res. 2017 Jan 3;36(1):1.

BACKGROUND: More effective chemotherapies are urgently needed for bladder cancer, a major cause of morbidity and mortality worldwide. We therefore explored the efficacy of the combination of gemcitabine and AZD7762, a checkpoint kinase 1/2 (CHK1/2) inhibitor, for bladder cancer. METHODS: Viability, clonogenicity, cell cycle distribution and apoptosis were assessed in urothelial cancer cell lines and various non-malignant urothelial cells treated with gemcitabine and AZD7762. DNA damage was assessed by gammaH2A.X and 53-BP1 staining and checkpoint activation was followed by Western blotting. Pharmacological inhibition of CHK1 and CHK2 was compared to downregulation of either CHK1 or CHK2 using siRNAs. RESULTS: Combined use of gemcitabine and AZD7762 synergistically reduced urothelial carcinoma cell viability and colony formation relative to either single treatment. Non-malignant urothelial cells were substantially less sensitive to this drug combination. Gemcitabine plus AZD7762 inhibited cell cycle progression causing cell accumulation in S-phase. Moreover, the combination induced pronounced levels of apoptosis as indicated by an increase in the fraction of sub-G1 cells, in the levels of cleaved PARP, and in caspase 3/7 activity. Mechanistic investigations showed that AZD7762 treatment inhibited the repair of gemcitabine-induced double strand breaks by interference with CHK1, since siRNA-mediated depletion of CHK1 but not of CHK2 mimicked the effects of AZD7762. CONCLUSIONS: AZD7762 enhanced sensitivity of urothelial carcinoma cells to gemcitabine by inhibiting DNA repair and disturbing checkpoints. Combining gemcitabine with CHK1 inhibition holds promise for urothelial cancer therapy.

Description

AZD-7762 is a potent ATP-competitive checkpoint kinase (Chk) inhibitor in with an IC50 of 5 nM for Chk1.

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