AZD8186

• CAS: 1627494-13-6
• Catalog Number: ACM1627494136
• Category: Inhibitors
• Molecular Weight: 457.40
• Molecular Formula: C24H25F2N3O4
• 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.
• Synonyms: AZD8186; AZD 8186; AZD-8186
• IUPAC Name: (R)-8-(1-((3,5-difluorophenyl)amino)ethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide
• Canonical SMILES: O=C(N(C)C)C1=CC([C@@H](C)NC2=CC(F)=CC(F)=C2)=C3C(C(C=C(O3)N4CCOCC4)=O)=C1
• 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
• InChI Key: LMJFJIDLEAWOQJ-CQSZACIVSA-N
• Solubility: Soluble in DMSO, not in water
• Appearance: Solid powder
• Shelf Life: >2 years if stored properly
• Storage: Dry, dark and at 0-4 °C for short term (days to weeks) or -20 °C for long term (months to years).
• 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).
• Drug Formulation: This drug may be formulated in DMSO
• Elemental Analysis: C, 63.01; H, 5.51; F, 8.31; N, 9.19; O, 13.99
• Exact Mass: 457.18131
• HS Tariff Code: 2934.99.9001
• 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
• Shipping: 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.
• Stock Solution Storage: 0-4 °C for short term (days to weeks), or -20 °C for long term (months).