Saracatinib (AZD0530)

Saracatinib (AZD0530) is a potent Src inhibitor with IC50 of 2.7 nM, and potent to c-Yes, Fyn, Lyn, Blk, Fgr and Lck; less active for Abl and EGFR (L858R and L861Q). Phase 2/3.

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Saracatinib (AZD0530) Chemical Structure

Saracatinib (AZD0530) Chemical Structure
Molecular Weight: 542.03

Validation & Quality Control

Product Citations(27)

Customer Reviews(8)

Quality Control & MSDS

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Product Information

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  • Saracatinib (AZD0530) Mechanism
  • Combination Therapy
    Combination Therapy

Product Description

Biological Activity

Description Saracatinib (AZD0530) is a potent Src inhibitor with IC50 of 2.7 nM, and potent to c-Yes, Fyn, Lyn, Blk, Fgr and Lck; less active for Abl and EGFR (L858R and L861Q). Phase 2/3.
Targets c-Src [2] LCK [2] c-YES [2] EGFR (L861Q) [2] Lyn [2]

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IC50 2.7 nM <4 nM 4 nM 4 nM 5 nM
In vitro Saracatinib also potently inhibits other Src tyrosine kinase family members including c-Yes, Fyn, Lyn, Blk, Fgr, and Lck with IC50 from 4-10 nM. Saracatinib sensitively inhibits Src Y530F NIH 3T3 with IC50 of 80 nM. Saracatinib significantly impairs the invasion of HT1080 cells through a 3-dimensional collagen matrix and completely inhibits EGF-induced cell scattering in NBT-II bladder cancer cells. [1] Saracatinib potent inhibits Src activation in DU145 and PC3 cells, which through inhibition of Y419 phosphorylation. Saracatinib inhibits the growth of prostate cancer including PC3, DU145, CWR22Rv1 and LNCaP, while Saracatinib shows low activity in LAPC-4, PZ-HPV7 and RWPE-1 cells. Saracatinib induces cell cycle arrest at G1/S but not caspase 3 cleavages. Saracatinib also significantly inhibits DU145 and PC3 migration in the Boyden chamber. [2] Saracatinib gives a potent and sustained blockage of AKT and enhances the sensitivity to irradiation in A549 and Calu-6 cells. [3] Saracatinib inhibits osteoclast in activity, resorption and formation. Saracatinib also reversibly prevents osteoclast precursor migration. [4]
In vivo Saracatinib shows great tumor growth inhibition in Src3T3 allografts and a moderate growth delay in Calu-6, MDA-MB-231, AsPc-1 and BT474C xenografts. [1] Saracatinib shows great antitumor activity in orthotopic DU145 xenograft mice at a dose of 25mg/kg (orally administered, daily). [2]
Features The 1st Src inhibitor to show inhibition of the Src pathway in human tumor tissue.

Protocol(Only for Reference)

Kinase Assay: [1]

Kinase Assay IC50 of tyrosine kinase activity is measured by an enzyme-linked immunosorbent assay (ELISA) with recombinant catalytic domains of a panel of receptor and non-receptor tyrosine kinases (in some cases only part of the catalytic domain is used). Saracatinib dose ranges from 0.001-10 mM. Specificity assays against a panel of serine/threonine kinases are performed using a filter capture assay with 32P. Briefly, multidrop 384 plates containing 0.5 μL Saracatinib or controls (DMSO) alone or pH 3.0 buffer controls) are incubated with 15 μL of enzyme plus peptide/protein substrate for 5 min before the reaction is initiated by the addition of 10 μL of 20 mM Mg-ATP. For all enzymes the final concentration is approximated to the Michaelis constant (Km). Assays are carried out for 30min at room temperature before termination by the addition of 5 μL orthophosphoric acid. After mixing, the well contents are harvested onto a P81 Unifilter plate, using orthophosphoric acid as the wash buffer. Then IC50 is calculated.

Cell Assay: [1]

Cell lines PC3, DU145, CWR22Rv1, LNCaP, LAPC-4, PZ-HPV7 and RWPE-1 cells
Concentrations 62.5 nM - 16 mM
Incubation Time 1, 3 and 5 days
Method Cells are seeded at a density of 2× 103 in 96-well plates and incubated overnight. Then Saracatinib (62.5 nM-16 mM) is added to the cells. After 1, 3 and 5 days, culture medium is removed followed by addition of 0.2 mL DMSO per well and continuous shaking of plates at 200 rotations per minute for 15min. Then IC50 is measured by MTT metho

Animal Study: [1]

Animal Models CB17 mice are implanted with DU145 cells.
Formulation Dissolved in 0.5% hydroxypropyl methylcellulose, 0.1% Tween 80
Dosages 25 mg/kg
Administration Orally administered daily
Solubility 0.5% methylcellulose/0.2% Tween 80, , 30 mg/mL
* 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.

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

SpeciesBaboonDogMonkeyRabbitGuinea pigRatHamsterMouse
Weight (kg)121031.80.40.150.080.02
Body Surface Area (m2)0.60.50.240.150.050.0250.020.007
Km factor202012128653
Animal A (mg/kg) = Animal B (mg/kg) multiplied by  Animal B Km
Animal A Km

For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.

Rat dose (mg/kg) = mouse dose (22.4 mg/kg) ×  mouse Km(3)  = 11.2 mg/kg
rat Km(6)
1

References

[1] Chang YM, Oncogene, 2008, 27(49), 6365-6375.

[2] Green TP, et al. Mol Oncol, 2009, 3(3), 248-261.

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Clinical Trial Information( data from http://clinicaltrials.gov, updated on 2014-08-23)

NCT Number Recruitment Conditions Sponsor
/Collaborators
Start Date Phases
NCT02167256 Not yet recruiting Alzheimers Disease Yale University July 2014 Phase 2
NCT02116712 Recruiting Pulmonary Lymphangioleiomyomatosis Baylor College of Medicine|Tony Eissa|University of Texas|University of Cincinnati March 2014 Phase 1
NCT02085603 Recruiting Cancer Sheffield Teaching Hospitals NHS Foundation Trust|AstraZeneca March 2014 Phase 2
NCT01864655 Completed Alzheimers Disease Yale University|Stephen M. Strittmatter July 2013 Phase 1
NCT01196741 Completed Ovarian Cancer|Fallopian Tube Cancer|Primary Peritoneal Cancer University College, London|AstraZeneca|Cancer Research UK March 2011 Phase 2|Phase 3

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Chemical Information

Download Saracatinib (AZD0530) SDF
Molecular Weight (MW) 542.03
Formula

C27H32ClN5O5

CAS No. 379231-04-6
Storage 3 years -20℃Powder
6 months-80℃in DMSO
Synonyms
Solubility (25°C) * In vitro DMSO 100 mg/mL (184 mM)
Water <1 mg/mL (<1 mM)
Ethanol 100 mg/mL (184 mM)
In vivo 0.5% methylcellulose/0.2% Tween 80, 30 mg/mL
* <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.
Chemical Name N-(5-chlorobenzo[d][1,3]dioxol-4-yl)-7-(2-(4-methylpiperazin-1-yl)ethoxy)-5-(tetrahydro-2H-pyran-4-yloxy)quinazolin-4-amine

Research Area

Customer Reviews (8)


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Rating
Source J Biomol Screen, 2013, 18(1), 54-66. Saracatinib (AZD0530) purchased from Selleck
Method 3D Tumor Growth Assay
Cell Lines PC-3M cells
Concentrations 0-10 uM
Incubation Time 7 d
Results Reduction of colony size was observed for a number of established anticancer drugs, and IC 50 values for those reference compounds were determined based on the average area size of the cluster. IC 50 values were determined in two independent experiments and were quite reproducible.

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Rating
Source J Biomol Screen, 2013, 18(1), 54-66. Saracatinib (AZD0530) purchased from Selleck
Method 3D Tumor Growth Assay
Cell Lines PC-3M cells
Concentrations 0-10uM
Incubation Time 7 day
Results Reduction of colony size was observed for a number of established anticancer drugs, and IC 50 values for those reference compounds were determined based on the average area size of the cluster. IC 50 values were determined in two independent experiments and were quite reproducible.

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Rating
Source Translational Oncology, 2011, 4, 92-100. Saracatinib (AZD0530) purchased from Selleck
Method Western Blot
Cell Lines Hs683 cells
Concentrations 10 μM
Incubation Time 4 d
Results Figure 4 shows that AZD0530 prevented TMZ-induced soluble caveolin-1 expression but did not change basal levels of soluble caveolin-1 in Hs683 GBM cells. In contrast, erlotinib increased soluble caveolin-1 expression to a similar degree as TMZ in these Hs683 GBM cells.

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Rating
Source Mol Cancer Res, 2011, 9, 249-258. Saracatinib (AZD0530) purchased from Selleck
Method Cell Viability Assay
Cell Lines MDA-MB-231/1205Lu cells
Concentrations 50 uM
Incubation Time 1 h
Results To verify this observation, we used a second Src inhibitor, AZD0530, which also caused cell rounding (data not shown) and TRAIL sensitization.

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Rating
Source Dr. Shuxin Han of Kent State University. Saracatinib (AZD0530) purchased from Selleck
Method IP assay, Q-PCR assay
Cell Lines Primary human hepatocytes
Concentrations 5 μM
Incubation Time 6 h
Results

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Rating
Source Cancer Biol Ther, 2011, 12(3), 215-28. Saracatinib (AZD0530) purchased from Selleck
Method Cell viability assays
Cell Lines embryonic fibroblasts
Concentrations 125 nM
Incubation Time 48 h
Results In transformed embryonic fibroblasts genetically deleted for toxic BH3 domain proteins BAX and BAK, but not deleted for BID, the combination of a SRC inhibitor (AZD0530; PP2; dasatinib) with a CHK1 inhibitor (UCN-01, AZD7762) was unable to cause cell killing.

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Rating
Source Cancer Res, 2011, 71(24), 7547-57. Saracatinib (AZD0530) purchased from Selleck
Method Cell proliferation assay
Cell Lines Huh7 cells/SK-Hep1 cells
Concentrations 1 μmol/L
Incubation Time
Results Results of cell proliferation assay showed that saracatinib treatment could significantly atten-uate promotive hepatoma cellular proliferation conferred by stable LHBs expression in Huh7 and SK-Hep1 cells (Fig. A and B).

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Rating
Source Cancer Res, 2011, 71(24), 7547-57. Saracatinib (AZD0530) purchased from Selleck
Method Tumor xenograft experiments
Cell Lines tumor xenografted nude mice
Concentrations 25 mg/kg
Incubation Time 4 weeks
Results tumor xenograft experiments in nude mice showed that orally saracatinib administration could also alleviate instigative tumor formation induced by stable LHBs expression in Huh7 and SK-Hep1 cells .

Product Citations (27)

Tech Support & FAQs

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