2. Stem Cell/Wnt
  3. Wnt β-catenin
  4. AZ1366

AZ1366 is an orally active tankyrase inhibitor. AZ1366 stabilizes Axin2, reduces NuMA levels, disrupts the interaction between tankyrase and NuMA, induces G2/M phase arrest, inhibits the Wnt pathway, and downregulates the expression of β-catenin-dependent genes. AZ1366 inhibits tumor growth in colorectal cancer xenograft models. AZ1366 synergistically inhibits the proliferation of non-small cell lung cancer cells, improves tumor control and significantly prolongs survival in orthotopic non-small cell lung cancer mouse models. AZ1366 is applicable to research related to colorectal cancer and non-small cell lung cancer.

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AZ1366

AZ1366 Chemical Structure

CAS No. : 1645286-58-3

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Description

AZ1366 is an orally active tankyrase inhibitor. AZ1366 stabilizes Axin2, reduces NuMA levels, disrupts the interaction between tankyrase and NuMA, induces G2/M phase arrest, inhibits the Wnt pathway, and downregulates the expression of β-catenin-dependent genes. AZ1366 inhibits tumor growth in colorectal cancer xenograft models. AZ1366 synergistically inhibits the proliferation of non-small cell lung cancer cells, improves tumor control and significantly prolongs survival in orthotopic non-small cell lung cancer mouse models. AZ1366 is applicable to research related to colorectal cancer and non-small cell lung cancer[1][2].

In Vitro

AZ1366 (0-5 μM; 48-72 h) enhances the antiproliferative effect of SN-38 (HY-13704) and induces S-phase and G2/M-phase arrest in the RKO colorectal cancer cell line[1].
AZ1366 (Compound 9) (0-100 nM; 24-48 h) inhibits the canonical Wnt signaling pathway in HCC4006 non-small cell lung cancer cells by stabilizing Axin-1 and reducing the mRNA expression of β-catenin target genes[2].
AZ1366 (0-90 nM; 3 days) synergistically enhances the antiproliferative effect of EGFR inhibitors in HCC4006 non-small cell lung cancer cells[2].
AZ1366 (0-90 nM; 72 h) acts synergistically with Gefitinib (HY-50895) to inhibit the proliferation of Wnt-responsive non-small cell lung cancer cell lines (HCC4006, H3255, H1650). It blocks the Wnt3a-induced canonical Wnt signaling pathway in HCC4006 cells, but exerts no such effect on the non-Wnt-responsive PC9 cells[2].

MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.

AZ1366 Related Antibodies

RT-PCR[2]

Cell Line: HCC4006 non-small cell lung cancer (NSCLC) cells
Concentration: 0, 10, 20, 50, 100 nM
Incubation Time: 24 h
Result: Decreased mRNA levels of β-catenin dependent targets Survivin, c-Myc, and Axin2 in a dose-dependent manner.

Western Blot Analysis[2]

Cell Line: HCC4006 non-small cell lung cancer (NSCLC) cells
Concentration: 0, 10, 20, 50, 100 nM
Incubation Time: 48 h
Result: Stabilized Axin-1 in a dose-dependent manner.

Cell Proliferation Assay[2]

Cell Line: HCC4006 NSCLC cells
Concentration: 0, 10, 30, 90 nM
Incubation Time: 3 days, followed by 4 days outgrowth
Result: Dose-dependently augmented the anti-proliferative effects of gefitinib, erlotinib, and osimertinib.

Cell Proliferation Assay[2]

Cell Line: HCC4006 and H1650 NSCLC cells
Concentration: 0, 10, 30, 90 nM
Incubation Time: 3 days (proliferation assay); 72 h (Western Blot Analysis)
Result: Dose-dependently enhanced Gefitinib-induced proliferation inhibition in scramble shRNA-expressing HCC4006 and H1650 cells.
Completely abolished synergistic effect in Axin-1 knockdown cells.
Showed greater growth inhibitory effects on scramble shRNA-expressing cells compared to Axin-1 knockdown cells.
In Vivo

AZ1366 (50 mg/kg; p.o.; daily, 5 days) induces significant tumor growth inhibition in 33% of colorectal cancer patient-derived xenograft models. Its mechanism of action involves Axin2 stabilization, CDC2 phosphorylation, induction of activated caspase-3, and reduction of NuMA levels. When combined with Irinotecan (HY-16562), it significantly inhibits tumor growth[1].
Combination of AZ1366 (25-50 mg/kg; p.o.; 5 days per week) with Gefitinib significantly prolongs the median survival and delays tumor growth in Wnt-responsive orthotopic HCC4006 and H1650 non-small cell lung cancer xenograft models[2].

MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.

Animal Model: athymic (nu+/nu+) (4-6 week old female; subcutaneous patient-derived colorectal adenocarcinoma xenografts, F1-F3 generations)[1]
Dosage: 50 mg/kg (efficacy)
Administration: p.o.; 5 days;
Result: Induced significant tumor growth reduction in 6 out of 18 colorectal cancer patient-derived xenograft models.
Reached a tumor growth inhibition index (TGII) of 10% in the CRC040 model.
Caused plasma and tumor concentrations to peak within 1 hour and become undetectable by 30 hours in PK/PD analysis of CRC040.
Elevated Axin2 protein levels as early as 15 minutes, peaked at 8 hours, then declined in CRC040.
Increased phosphorylation of CDC2 at 8 hours and cleaved caspase-3 at 48 hours in CRC040.
Did not reduce active β-catenin or c-Myc levels in CRC040, nor nuclear β-catenin levels in CRC114.
Reduced NuMA protein levels, decreased the interaction between tankyrase and NuMA, and increased phosphorylation of CDC2 and CDK2 after 7 days of treatment in combination-sensitive models (CRC026, CRC147).
Stabilized Axin2 protein levels in all evaluated models but did not reduce WNT-dependent signaling (active β-catenin, CD44, Axin2, Jag1 gene expression).
Induced significant tumor growth reduction in 4 out of 18 irinotecan-resistant colorectal cancer patient-derived xenograft models (CRC010, CRC026, CRC114, CRC147) with elevated baseline tankyrase and NuMA levels.
Stabilized Axin2 protein levels, reduced NuMA protein levels, decreased the interaction between tankyrase and NuMA, and increased phosphorylation of CDC2 and CDK2 in combination-sensitive models.
Did not reduce WNT-dependent signaling (active β-catenin, CD44, Axin2, Jag1 gene expression).
Animal Model: Athymic nude mice (8-12 week old female; orthotopically implanted luciferase-tagged HCC4006 NSCLC cells, randomized when tumor reached 5×108 p/s) (orthotopically implanted luciferase-tagged H1650 NSCLC cells, randomized when tumor reached 5×108 p/s)[2]
Dosage: 25 mg/kg (combination with gefitinib; survival, tumor growth); 50 mg/kg (combination with gefitinib; no survival benefit); 25 mg/kg (single agent; no survival benefit)
Administration: p.o.; daily for 5 days per week
Result: Did not significantly change tumor burden at death or increase median survival as single agent.
Increased median survival from 92 days (gefitinib alone) to 152 days, significantly increased tumor doubling time, and slowed tumor growth when co-administered with gefitinib at 25 mg/kg.
Did not provide similar survival advantage when co-administered with gefitinib at 50 mg/kg.
Stabilized intratumoral Axin-1 at 24 and 72 hours post single-dose administration, with stabilization sustained through 72 hours but lost by 168 hours.
Did not significantly change tumor burden at death or increase median survival (41 days vs.
55 days for vehicle) as single agent.
Increased median survival from 59 days (gefitinib alone) to 168 days, significantly increased tumor doubling time, and slowed tumor growth when co-administered with gefitinib at 25 mg/kg.
Did not provide similar survival advantage when co-administered with gefitinib at 50 mg/kg.
Molecular Weight

416.48

Formula

C24H24N4O3
CAS No.
SMILES

O=C1N=C(NC=2C1=CC=CC2CO)C=3C=CC(=CC3)C=4C=NC(=CC4C)NCCOC
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Storage

Please store the product under the recommended conditions in the Certificate of Analysis.
Purity & Documentation
References
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  • Do most proteins show cross-species activity?

    Species cross-reactivity must be investigated individually for each product. Many human cytokines will produce a nice response in mouse cell lines, and many mouse proteins will show activity on human cells. Other proteins may have a lower specific activity when used in the opposite species.

Keywords:

AZ13661645286-58-3AZ 1366AZ-1366Wntβ-cateninBeta catenintankyrase inhibitorcolorectal cancernon-small cell lung cancerRKO colorectal cancer cellHCC4006 non-small cellH3255 cellH1650 cellathymic miceInhibitorinhibitorinhibit

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