WARNING: This product is for research use only, not for human or veterinary use.
MedKoo CAT#: 406260
Description: AZD8186 is and 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. It also 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. AZD8186 is currently under Phase I clinical trials.
MedKoo Cat#: 406260
Chemical Formula: C24H25F2N3O4
Exact Mass: 457.18131
Molecular Weight: 457.4
Elemental Analysis: C, 63.01; H, 5.51; F, 8.31; N, 9.19; O, 13.99
Synonym: AZD8186; AZD 8186; AZD-8186.
IUPAC/Chemical Name: (R)-8-(1-((3,5-difluorophenyl)amino)ethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide
InChi Key: LMJFJIDLEAWOQJ-CQSZACIVSA-N
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
SMILES Code: O=C(N(C)C)C1=CC([C@@H](C)NC2=CC(F)=CC(F)=C2)=C3C(C(C=C(O3)N4CCOCC4)=O)=C1
Appearance: Solid powder
Purity: >98% (or refer to the Certificate of Analysis)
Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.
Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).
Solubility: Soluble in DMSO, not in water
Shelf Life: >2 years if stored properly
Drug Formulation: This drug may be formulated in DMSO
Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).
HS Tariff Code: 2934.99.9001
|Biological target:||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 activity:||The increase in expression of IGF1R is accompanied by increased expression of the IRS1 protein in LNCaP (1.5-fold after one hour, 2.8-fold in 6 hours) and BT-549 cells (1.9-fold induction after 4 hours) (Figure 3C and S3K). In both models, mTOR activation is dependent on PI3Kβ, as demonstrated by the sensitivity of S6K phosphorylation to AZD8186 (Figure 3C, S3K). Activated S6K phosphorylates serine sites of IRS1 (S312 and/or S636/639) that causes the degradation of IRS1. Increased IRS1 expression in cells treated with AZD8186 was associated with decreased phosphorylation of IRS1 S636/639 and increased phosphorylation at Y612, a site that plays a role in the ability of IRS1 to activate PI3K (Figure 3C, S3K). These data suggest that inhibition of PI3Kβ relieves feedback inhibition of IGF and insulin signaling by increasing IGF1R and IRS1 expression and thus causing reactivation of PI3Kα. Reference: Cancer Cell. 2015 Jan 12; 27(1): 109–122. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4293347/|
|In vivo activity:||Treating 786-0 tumor mice xenografts, a PTEN-null renal cell adenocarcinoma cell line, with AZD8186 results in significant antitumor activity (Fig. 4A), and changes in FDG-PET uptake. This tumor is sensitive to AZD8186 at doses as low as 12.5 mg/kg. Examination of pathway biomarkers in this model showed that in addition to inhibition of pAKT, pPRAS40, pNDRG1, and pS6, downregulation of HMGCS1 and IDI1 was observed (Fig. 4B). These in vivo observations were consistent in vitro; expression of HMGCS1 was downregulated in 2D and 3D cultures. However, the degree of downregulation was greater in 3D and correlated with growth suppression (Supplementary Fig. S8A). 786-0 cells were insensitive to AZD8186 when grown in 2D, but sensitive in 3D culture conditions (Supplementary Fig. S8B). Although the effects in tumor models can vary between models, modulation of the cholesterol pathway is evident when AZD8186 delivers antitumor benefit. Reference: Clin Cancer Res. 2017 Dec 15;23(24):7584-7595. https://clincancerres.aacrjournals.org/content/23/24/7584.long|
|Solvent||Max Conc. mg/mL||Max Conc. mM|
The following data is based on the product molecular weight 457.4 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.
|Concentration / Solvent Volume / Mass||1 mg||5 mg||10 mg|
|1 mM||1.15 mL||5.76 mL||11.51 mL|
|5 mM||0.23 mL||1.15 mL||2.3 mL|
|10 mM||0.12 mL||0.58 mL||1.15 mL|
|50 mM||0.02 mL||0.12 mL||0.23 mL|
|Formulation protocol:||1. Schwartz S, Wongvipat J, Trigwell CB, Hancox U, Carver BS, Rodrik-Outmezguine V, Will M, Yellen P, de Stanchina E, Baselga J, Scher HI, Barry ST, Sawyers CL, Chandarlapaty S, Rosen N. Feedback suppression of PI3Kα signaling in PTEN-mutated tumors is relieved by selective inhibition of PI3Kβ. Cancer Cell. 2015 Jan 12;27(1):109-22. doi: 10.1016/j.ccell.2014.11.008. Epub 2014 Dec 24. PMID: 25544636; PMCID: PMC4293347. 2. Lynch JT, Polanska UM, Delpuech O, Hancox U, Trinidad AG, Michopoulos F, Lenaghan C, McEwen R, Bradford J, Polanski R, Ellston R, Avivar-Valderas A, Pilling J, Staniszewska A, Cumberbatch M, Critchlow SE, Cruzalegui F, Barry ST. Inhibiting PI3Kβ with AZD8186 Regulates Key Metabolic Pathways in PTEN-Null Tumors. Clin Cancer Res. 2017 Dec 15;23(24):7584-7595. doi: 10.1158/1078-0432.CCR-17-0676. Epub 2017 Oct 2. PMID: 28972046.|
|In vitro protocol:||1. Schwartz S, Wongvipat J, Trigwell CB, Hancox U, Carver BS, Rodrik-Outmezguine V, Will M, Yellen P, de Stanchina E, Baselga J, Scher HI, Barry ST, Sawyers CL, Chandarlapaty S, Rosen N. Feedback suppression of PI3Kα signaling in PTEN-mutated tumors is relieved by selective inhibition of PI3Kβ. Cancer Cell. 2015 Jan 12;27(1):109-22. doi: 10.1016/j.ccell.2014.11.008. Epub 2014 Dec 24. PMID: 25544636; PMCID: PMC4293347.|
|In vivo protocol:||1. Lynch JT, Polanska UM, Delpuech O, Hancox U, Trinidad AG, Michopoulos F, Lenaghan C, McEwen R, Bradford J, Polanski R, Ellston R, Avivar-Valderas A, Pilling J, Staniszewska A, Cumberbatch M, Critchlow SE, Cruzalegui F, Barry ST. Inhibiting PI3Kβ with AZD8186 Regulates Key Metabolic Pathways in PTEN-Null Tumors. Clin Cancer Res. 2017 Dec 15;23(24):7584-7595. doi: 10.1158/1078-0432.CCR-17-0676. Epub 2017 Oct 2. PMID: 28972046.|
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, Peru A, PlÃ© 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-chrom ene-6-carboxamide (AZD8186): A Potent and Selective Inhibitor of PI3Kβ and PI3Kδ for the treatment of PTEN-deficient cancers. J Med Chem. 2014 Dec 16. [Epub ahead of print] PubMed PMID: 25514658.
2: Hancox U, Cosulich S, Hanson L, Trigwell C, Lenaghan C, Ellston R, Dry H, Crafter C, Barlaam B, Fitzek M, Smith PD, Ogilvie D, D'Cruz C, Castriotta L, Wedge SR, Ward L, Powell S, Lawson M, Davies BR, Harrington EA, Foster E, Cumberbatch M, Green S, Barry ST. Inhibition of PI3Kβ signaling with AZD8186 inhibits growth of PTEN deficient breast and prostate tumour alone and in combination with docetaxel. Mol Cancer Ther. 2014 Nov 14. pii: molcanther.0406.2014. [Epub ahead of print] PubMed PMID: 25398829.
3: Marques RB, Aghai A, de Ridder CM, Stuurman D, Hoeben S, Boer A, Ellston RP, Barry ST, Davies BR, Trapman J, van Weerden WM. High Efficacy of Combination Therapy Using PI3K/AKT Inhibitors with Androgen Deprivation in Prostate Cancer Preclinical Models. Eur Urol. 2014 Sep 11. pii: S0302-2838(14)00806-9. doi: 10.1016/j.eururo.2014.08.053. [Epub ahead of print] PubMed PMID: 25220373.
AZD8186 is a novel potent small molecule that targets the lipid kinase PI3Kβ with selectivity vs PI3Kα. AZD8186 reduces pAKT-S473 in the PTEN deficient MDA-MB-468 cell line with an IC50 <5nM, while in the PI3Kα-dependent PIK3CA mutant line BT474 it is 200 fold less potent. AZD8186 also demonstrates cellular activity versus PI3Kβ, inhibiting IgM-dependent pAKT-S473 with an IC50 of 15nM.