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Purity: ≥98%
AZD8186 (also known as AZD) is a novel, potent and selective inhibitor of PI3Kβ (phosphatidylinositol 3-kinase β) with potential anticancer activity. It exhibits high selectivity for PI3K and PI3K over PI3K (IC50=675 nM) and inhibits PI3K and PI3K with IC50 values of 4 nM and 12 nM, respectively. In PTEN-deficient preclinical models, AZD8186 significantly inhibits tumor growth, especially when combined with anti-androgens or the dual mTORC1/2 inhibitor vistusertib (AZD2014). AZD8186 may be used to treat tumors that lack PTEN.
| Targets |
PI3Kβ (IC50 = 4 nM); PI3Kδ (IC50 = 12 nM); PI3Kα (IC50 = 35 nM); PI3Kγ (IC50 = 675 nM)
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|---|---|
| ln Vitro |
AZD8186 is a potent inhibitor of PI3Kβ with additional activity versus the PI3Kδ isoform. The absolute selectivity profile for PI3Ks is understated in biochemical assays due to the tight-binding kinetics of AZD8186. Selectivity for PI3Kβ and δ is >100-fold higher in 74 protein and lipid kinases than it is in 74 different protein and lipid kinase assays.
In a KinomeScan screen, AZD8186 at 10 M displayed no detectable binding to 442 additional kinases. In contrast to other off-target activity, AZD8186 exhibits selectivity for PI3K family kinases. MDA-MB-468 AZD8186 has an IC50 value of 3 nM in the PTEN-null line, where it prevents PI3Kβ-dependent activation of pAKT (Ser473). The PIK3CA-mutant line BT474c has a potency of 752 nM, showing preference for PI3Kβ over PI3Kα. When B cells are stimulated by IgM, PI3Kδ is activated, which phosphorylates AKT. With an IC50 value of 17 nM, AZD8186 prevents pAKT (Ser473) activation induced by IgM in JEKO cells. In tests for cell proliferation, IgM stimulated JEKO cell growth with an IC50 value of 228 nM, while AZD8186 inhibited MDA-MB-468 cell proliferation with a GI50 value of 65 nM. Its IC50 value of 1.981 M, which is consistent with its preference for PI3Kβ over PI3Kα, only inhibited the growth of BT474c cell lines[1].
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| ln Vivo |
Antitumor activity is evaluated in the PTEN-null TNBC models HCC70 and MDA-MB-468, as well as the prostate models PC3 and HID28, in order to evaluate the single-agent efficacy of AZD8186 in vivo. All four models are slowed down in growth by AZD8186 at doses of 50 and 25 mg/kg twice daily. At 25 and 50 mg/kg, HCC70 is inhibited at 62% (P 0.001) and 85% (P<0.001), respectively, and MDA-MB-468 is inhibited at 47% (P 0.001) and 76% (P<0.001), respectively, at the end of the study, with regression early in the study. PC3's effectiveness in the PTEN-null prostate model is less pronounced, with doses of 25 and 50 mg/kg inhibiting maximum growth by 59% (P 0.001) and 64% (P<0.001), respectively. In contrast, AZD8186 inhibits growth in the PTEN-null prostate explant model HID28 by 79% (P<0.001). When administered to mice, AZD8186 has a brief half-life and a PK profile that produces patchy coverage over a 24-hour period. Animals with PC3 tumors are co-dosed with AZD8186 in the presence of the Cyt P450 inhibitor ABT, which significantly lengthens the time of exposure. Additionally, a tumor growth reduction of 86% (P<0.005) was achieved in the PC3 model using 30 mg/kg of AZD8186+ABT[1].
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| Enzyme Assay |
The inhibition of PI3Kα, PI3Kβ, PI3Kγ and PI3Kδ human recombinant PI3K isoforms is evaluated using a Kinase-Glo Plus Assay Kit. 12 point half-log concentration-response curves with a top concentration of 100 μM are constructed by dispensing DMSO solubilised compounds into white 384-well medium-binding microplates using an Echo 555. 3 μL of the appropriate PI3K in Tris buffer (50 mM Tris pH7.4, 0.05% CHAPS, 2.1 mM DTT, and 10 mM MgCl2) is added.
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| Cell Assay |
AZD8186 is applied to cells for 2 hours at concentrations ranging from 3 to 0.01 μM . Following that, cells are lysed on ice using a buffer containing 0.5% Triton X-100, 3 mM EDTA, 3 mM EGTA, 50 mM NaF, 2 mM sodium orthovanadate, 270 mM sucrose, 10 mM β-glycerophosphate, and 5 mM sodium pyrophosphate. Sample loading buffer is used to dilute the lysates before they are separated on 4% to 12% Bis-Tris Novex gels, transferred to nitrocellulose membranes, and overnight probed with primary antibodies. Membranes are washed, then incubated with secondary antibodies that have been HRP-tagged before being observed[1].
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| Animal Protocol |
Mice：The female CB17 SCID mice ages 6 to 8 weeks are used. HID28 tumor fragments (about 40 mm3) from donor animals are aseptically implanted subcutaneously, at the level of the interscapular region, for the purpose of performing HID28 in vivo experiments. Male outbred athymic (nu/nu) mice, 18 to 25 g (HSD: Athymic Nude-Foxn1nu). For all animal studies, groups must contain a minimum of 8 animals each. AZD8186 is typically prepared once weekly as a suspension in HPMC/Tween and dosed once or twice daily (0 and 6-8 hours). Once a week, AZD8186 is prepared either without ABT at a concentration of 10 mg/mL in 10% DMSO, 60% tri-ethylene glycol (TEG), and 30% water for injection (WFI). AZD8186 is co-dosed with ABT at 0 hours for twice-daily dosing and given alone as the single formulation at 6 to 8 hours. On day 0, 24 hours before the administration of AZD8186, RP-56976 is administered as a single i.v. bolus dose at a rate of 0.1 mL/10 g. It is freshly formulated in physiologic saline at 1.5 mg/mL.
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| References | |
| Additional Infomation |
AZD-8186 is under investigation in clinical trial NCT03218826 (PI3Kbeta Inhibitor AZD8186 and Docetaxel in Treating Patients Advanced Solid Tumors With PTEN or PIK3CB Mutations That Are Metastatic or Cannot Be Removed by Surgery).
PI3Kbeta Inhibitor AZD8186 is an inhibitor of the beta isoform of phosphoinositide-3 kinase (PI3K), with potential antineoplastic activity. Upon administration, PI3Kbeta inhibitor AZD8186 selectively inhibits the activity of PI3Kbeta in the PI3K/Akt/mTOR signaling pathway, which may result in a decrease of tumor cell proliferation and induces cell death in PI3K-expressing cancer cells. By specifically targeting class I PI3K beta, this agent may be more efficacious and less toxic than pan PI3K inhibitors. PI3K-mediated signaling is often dysregulated in cancer cells and contributes to increased tumor cell growth, survival, and tumor resistance to a variety of antineoplastic agents. |
| Molecular Formula |
C24H25F2N3O4
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|---|---|
| Molecular Weight |
457.4698
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| Exact Mass |
457.181
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| Elemental Analysis |
C, 63.01; H, 5.51; F, 8.31; N, 9.19; O, 13.99
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| CAS # |
1627494-13-6
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| Related CAS # |
1627494-13-6
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| PubChem CID |
52913813
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| Appearance |
White to off-white solid powder
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| Density |
1.4±0.1 g/cm3
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| Boiling Point |
645.2±55.0 °C at 760 mmHg
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| Flash Point |
344.0±31.5 °C
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| Vapour Pressure |
0.0±1.9 mmHg at 25°C
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| Index of Refraction |
1.618
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| LogP |
2.79
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
8
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| Rotatable Bond Count |
5
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| Heavy Atom Count |
33
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| Complexity |
748
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| Defined Atom Stereocenter Count |
1
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| SMILES |
FC1C([H])=C(C([H])=C(C=1[H])N([H])[C@]([H])(C([H])([H])[H])C1=C([H])C(C(N(C([H])([H])[H])C([H])([H])[H])=O)=C([H])C2C(C([H])=C(N3C([H])([H])C([H])([H])OC([H])([H])C3([H])[H])OC1=2)=O)F
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| InChi Key |
LMJFJIDLEAWOQJ-CQSZACIVSA-N
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| InChi Code |
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
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| Chemical Name |
(R)-8-(1-((3,5-difluorophenyl)amino)ethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide
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| Synonyms |
AZD-8186; AZD8186; AZD 8186
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO: ~91 mg/mL warming (198.9 mM)
Water: <1 mg/mL Ethanol: 35 mg/mL warming (76.5 mM) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: 15 mg/mL (32.79 mM) in 10% DMSO/60% tri-ethylene glycol (TEG)/30% water (add these co-solvents sequentially from left to right, and one by one), clear solution; with sonication.
Solubility in Formulation 2: ≥ 2.75 mg/mL (6.01 mM) (saturation unknown) in 5% DMSO + 40% PEG300 + 5% Tween80 + 50% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.75 mg/mL (6.01 mM) (saturation unknown) in 5% DMSO + 95% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. Solubility in Formulation 4: ≥ 2.08 mg/mL (4.55 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL of PEG300 and mix evenly; then add 50 μL of Tween-80 to the above solution and mix evenly; then add 450 μL of normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 5: ≥ 2.08 mg/mL (4.55 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. Solubility in Formulation 6: ≥ 2.08 mg/mL (4.55 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. Solubility in Formulation 7: 10%DMSO+ 60% TEG+ 30% WFI: 16mg/mL |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.1859 mL | 10.9297 mL | 21.8594 mL | |
| 5 mM | 0.4372 mL | 2.1859 mL | 4.3719 mL | |
| 10 mM | 0.2186 mL | 1.0930 mL | 2.1859 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
| NCT Number | Status | Interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT03218826 | Active Recruiting |
Drug: Docetaxel Drug: PI3Kbeta Inhibitor AZD8186 |
Advanced Breast Carcinoma Advanced Prostate Carcinoma |
National Cancer Institute (NCI) |
March 16, 2018 | Phase 1 |
| NCT04526470 | Recruiting | Drug: Alpelisib Drug: Paclitaxel |
Solid Tumor Stomach Cancer |
Seoul National University Bundang Hospital |
September 1, 2020 | Phase 1 hase 2 |
| NCT01884285 | Completed | Drug: Part A: AZD8186 monotherapy Drug: Part B: AZD8186 monotherapy |
Advanced Castrate-resistant Prostate Cancer CRPC Squamous Non-Small Cell Lung Cancer sqNSCLC |
AstraZeneca | July 9, 2013 | Phase 1 |
Activity of AZD8186. Mol Cancer Ther. 2015, 14(1), 48-58. |
In vivo activity of AZD8186 |
AZD8186 combines with docetaxel. |
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