AZD8186Potent and selective inhibitor of PI3Kβ and PI3Kδ CAS# 1627494-13-6 |
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Quality Control & MSDS
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| Cas No. | 1627494-13-6 | SDF | Download SDF |
| PubChem ID | 52913813 | Appearance | Powder |
| Formula | C24H25F2N3O4 | M.Wt | 457.47 |
| Type of Compound | N/A | Storage | Desiccate at -20°C |
| Solubility | DMSO : ≥ 35 mg/mL (76.51 mM) *"≥" means soluble, but saturation unknown. | ||
| Chemical Name | 8-[(1R)-1-(3,5-difluoroanilino)ethyl]-N,N-dimethyl-2-morpholin-4-yl-4-oxochromene-6-carboxamide | ||
| SMILES | CC(C1=C2C(=CC(=C1)C(=O)N(C)C)C(=O)C=C(O2)N3CCOCC3)NC4=CC(=CC(=C4)F)F | ||
| Standard InChIKey | LMJFJIDLEAWOQJ-CQSZACIVSA-N | ||
| Standard InChI | InChI=1S/C24H25F2N3O4/c1-14(27-18-11-16(25)10-17(26)12-18)19-8-15(24(31)28(2)3)9-20-21(30)13-22(33-23(19)20)29-4-6-32-7-5-29/h8-14,27H,4-7H2,1-3H3/t14-/m1/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. |
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| 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. |
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| 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. | ||
| Description | AZD8186 is a PI3K inhibitor, which potently inhibits PI3Kβ (IC50=4 nM) and PI3Kδ (IC5050=12 nM) with selectivity over PI3Kα (IC50=35 nM) and PI3Kγ (IC50=675 nM).In Vitro:AZD8186 is a potent inhibitor of PI3Kβ with additional activity versus the PI3Kδ isoform. Tight-binding kinetics of AZD8186 means biochemical assays underestimate the absolute selectivity profile for PI3Ks. In a broad panel of protein and lipid kinase assays selectivity for PI3Kβ and δ is >100-fold versus 74 protein and lipid kinases. At 10 μM, AZD8186 had no significant binding to 442 other kinases in a KinomeScan screen. AZD8186 shows selectivity for PI3K family kinases, no other off-target activity is detected. In the PTEN-null line, MDA-MB-468 AZD8186 inhibits PI3Kβ-dependent activation of pAKT (Ser473) with an IC50 value of 3 nM. Potency in the PIK3CA-mutant line BT474c is 752 nM demonstrating selectivity for PI3Kβ over PI3Kα. IgM mediated stimulation of B cells results in phosphorylation of AKT through activation of PI3Kδ. AZD8186 inhibits IgM-stimulated phosphorylation of pAKT (Ser473) activation in JEKO cells with an IC50 value of 17 nM. In cell proliferation assays, AZD8186 inhibits proliferation of MDA-MB-468 cells with a GI50 value of 65 nM, IgM stimulated JEKO cell growth with an IC50 value of 228 nM. It only inhibited BT474c cell growth with an IC50 value of 1.981 μM consistent with its selectivity for PI3Kβ over PI3Kα[1].In Vivo:To assess single-agent efficacy of AZD8186 in vivo, antitumor activity is assessed in the PTEN-null TNBC models HCC70 and MDA-MB-468, and the prostate models PC3 and HID28. At 50 and 25 mg/kg twice a day, AZD8186 inhibits the growth of all four models. At 25 and 50 mg/kg, HCC70 is inhibited at 62% (P<0.001) and 85% (P<0.001), respectively, MDA-MB-468 is inhibited at 47% (P<0.001) and 76% (P<0.001), respectively, at end at of study, with regression early in the study. Efficacy in the PTEN-null prostate model, PC3 is less pronounced with 25 and 50 mg/kg giving maximal growth inhibition of 59% (P<0.001) and 64% (P<0.001), respectively. In contrast, AZD8186 gives 79% (P<0.001) growth inhibition in the PTEN-null prostate explant model HID28. In mouse, AZD8186 has a short half-life delivering a PK profile that results in intermittent cover over a 24 hours dosing interval. To increase the time of exposure, animals bearing PC3 tumors are co-dosed with AZD8186 in the presence of the Cyt P450 inhibitor ABT, which results in significantly increased exposure. This also increased the efficacy in the PC3 model with 86% (P<0.005) reduction in tumor growth achieved with 30 mg/kg AZD8186+ABT[1]. References: | |||||
AZD8186 Dilution Calculator
AZD8186 Molarity Calculator
| 1 mg | 5 mg | 10 mg | 20 mg | 25 mg | |
| 1 mM | 2.1859 mL | 10.9297 mL | 21.8594 mL | 43.7187 mL | 54.6484 mL |
| 5 mM | 0.4372 mL | 2.1859 mL | 4.3719 mL | 8.7437 mL | 10.9297 mL |
| 10 mM | 0.2186 mL | 1.093 mL | 2.1859 mL | 4.3719 mL | 5.4648 mL |
| 50 mM | 0.0437 mL | 0.2186 mL | 0.4372 mL | 0.8744 mL | 1.093 mL |
| 100 mM | 0.0219 mL | 0.1093 mL | 0.2186 mL | 0.4372 mL | 0.5465 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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Description:
IC50: 0.003 μM for PI3Kβ and 0.017 μM for PI3Kδ
The PI3K-Akt signaling pathway plays a critical role in cell growth, proliferation, motility, and survival. In human cancer, this pathway is activated by several mechanisms, including somatic mutations, deletions, and amplifications. Class I PI3Ks are further divided into class IA enzymes (PI3Kα, PI3Kβ, and PI3Kδ) and class IB enzymes (PI3Kγ). AZD8186 is a potent and selective inhibitor of PI3Kβ and PI3Kδ.
In vitro: AZD8186 gave potent inhibition of p-Akt in cells sensitive to PI3Kβ inhibition and in cells sensitive to PI3Kδ inhibition but not to cells sensitive to PI3Kα inhibition. The overall kinase selectivity of AZD8186 was evaluated in several panels of recombinant protein and lipid kinase assays. 13 did not show significant activity against a panel of 59 protein kinases tested at 1 μM [1].
In vivo: The antitumor activity of AZD8186 was evaluated in the PTEN deficient PC3 prostate tumor xenograft model in nude mice, either at 100 mg/kg b.i.d. without ABT coadministration, or at 60, 30, and 10 mg/mg b.i.d. with ABT coadministration. Higher inhibition was seen in the 60 and 30 mg/kg groups with ABT coadministration than in the 100 mg/kg group without ABT coadministration [1].
Clinical trial: AZD8186 was selected as a clinical candidate for treatment of PTENdeficient cancers and has recently entered phase I clinical trials [2].
Reference:
[1] Barlaam B, Cosulich S, Degorce S, Fitzek M, Green S, Hancox U, Lambert-van der Brempt C, Lohmann JJ, Maudet M, Morgentin R, Pasquet MJ, Péru A, Plé P, Saleh T, Vautier M, Walker M, Ward L, Warin N. Discovery of (R)-8-(1-(3,5-difluorophenylamino)ethyl)-N,N-dimethyl -2-morpholino-4-oxo-4H-chromene-6-carboxamide (AZD8186): a potent and selective inhibitor of PI3Kβ and PI3Kδ for the treatment of PTEN-deficient cancers. J Med Chem. 2015 Jan 22;58(2):943-62.
[2] https://clinicaltrials. gov/ct2/show/NCT01884285?term=AZD8186&rank=1
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Inhibition of PI3Kbeta signaling with AZD8186 inhibits growth of PTEN-deficient breast and prostate tumors alone and in combination with docetaxel.[Pubmed:25398829]
Mol Cancer Ther. 2015 Jan;14(1):48-58.
Loss of PTEN protein results in upregulation of the PI3K/AKT pathway, which appears dependent on the PI3Kbeta isoform. Inhibitors of PI3Kbeta have potential to reduce growth of tumors in which loss of PTEN drives tumor progression. We have developed a small-molecule inhibitor of PI3Kbeta and PI3Kdelta (AZD8186) and assessed its antitumor activity across a panel of cell lines. We have then explored the antitumor effects as single agent and in combination with docetaxel in triple-negative breast (TNBC) and prostate cancer models. In vitro, AZD8186 inhibited growth of a range of cell lines. Sensitivity was associated with inhibition of the AKT pathway. Cells sensitive to AZD8186 (GI50 < 1 mumol/L) are enriched for, but not exclusively associated with, PTEN deficiency. In vivo, AZD8186 inhibits PI3K pathway biomarkers in prostate and TNBC tumors. Scheduling treatment with AZD8186 shows antitumor activity required only intermittent exposure, and that increased tumor control is achieved when AZD8186 is used in combination with docetaxel. AZD8186 is a potent inhibitor of PI3Kbeta with activity against PI3Kdelta signaling, and has potential to reduce growth of tumors dependent on dysregulated PTEN for growth. Moreover, AZD8186 can be combined with docetaxel, a chemotherapy commonly used to treat advanced TBNC and prostate tumors. The ability to schedule AZD8186 and maintain efficacy offers opportunity to combine AZD8186 more effectively with other drugs.
The use of (18)F-fluorodeoxyglucose positron emission tomography ((18)F-FDG PET) as a pathway-specific biomarker with AZD8186, a PI3Kbeta/delta inhibitor.[Pubmed:27515445]
EJNMMI Res. 2016 Dec;6(1):62.
BACKGROUND: The phosphatidylinositol 3 kinase (PI3K) signalling pathway is frequently altered in human cancer and a promising therapeutic target. AZD8186 (AstraZeneca) is a PI3Kbeta/delta inhibitor, currently in phase 1 clinical trials. (18)F-fluorodeoxyglucose positron emission tomography ((18)F-FDG PET) is often used as a biomarker for inhibitors targeting the PI3K axis because of the association of this pathway with glucose metabolism. In this study, we assessed if (18)F-FDG PET could be used as a pharmacodynamic marker to monitor PI3Kbeta inhibition by AZD8186, and hence have potential as a clinical biomarker of PI3Kbeta pathway activation, and for patient selection. (18)F-FDG PET scans were performed in nude mice bearing 786-0 renal, U87-MG glioma, and BT474C breast xenograft models. Mice were fasted prior to imaging and static (18)F-FDG PET imaging was performed. Tumour growth was monitored throughout each study, and at the end of the imaging procedure, tumours were taken and a full pharmacodynamic analysis performed. RESULTS: Results showed that in PTEN null tumour xenograft models, 786-0 and U87-MG, the PI3Kbeta inhibitor AZD8186 reduces (18)F-FDG uptake at a dose of 50 mg/kg, the same dose which causes tumour inhibition, while it has no impact in a PI3Kalpha mutant tumour xenograft BT474C. Consistent with the change in (18)F-FDG uptake, AZD8186 also modulated AKT and associated glucose pathway biomarkers in the PTEN null tumour xenografts but not in PTEN wild-type tumours. CONCLUSIONS: Our pre-clinical studies support the use of (18)F-FDG PET imaging as a sensitive and non-invasive pharmacodynamic biomarker for use in clinical studies with AZD8186.
Discovery of (R)-8-(1-(3,5-difluorophenylamino)ethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chrom ene-6-carboxamide (AZD8186): a potent and selective inhibitor of PI3Kbeta and PI3Kdelta for the treatment of PTEN-deficient cancers.[Pubmed:25514658]
J Med Chem. 2015 Jan 22;58(2):943-62.
Several studies have highlighted the dependency of PTEN deficient tumors to PI3Kbeta activity and specific inhibition of PI3Kdelta has been shown activity against human B-cell cancers. We describe the discovery and optimization of a series of 8-(1-anilino)ethyl)-2-morpholino-4-oxo-4H-chromene-6-carboxamides as PI3Kbeta/delta inhibitors, which led to the discovery of the clinical candidate 13, also known as AZD8186. On the basis of the lower lipophilicity of the chromen-4-one core compared to the previously utilized pyrido[1,2-a]pyrimid-4-one core, this series of compounds displayed high metabolic stability and suitable physical properties for oral administration. Compound 13 showed profound pharmacodynamic modulation of p-Akt in PTEN-deficient PC3 prostate tumor bearing mice after oral administration and showed complete inhibition of tumor growth in the mouse PTEN-deficient PC3 prostate tumor xenograft model. 13 was selected as a clinical candidate for treatment of PTEN-deficient cancers and has recently entered phase I clinical trials.
