AZD8835
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MedKoo CAT#: 206479

CAS#: 1620576-64-8

Description: AZD8835 is a potent and selective inhibitor of PI3Kalpha and PI3Kdelata with excellent general kinase selectivity. AZD8835 displayed low metabolic turnover and suitable physical properties for oral administration. At the enzyme level, AZD8835 is a potent mixed inhibitor of PI3Kα (IC50 0.0062 μM) and PI3Kδ (IC50 0.0057 μM), with selectivity against PI3Kβ (IC50 0.431 μM) and PI3Kγ (IC50 0.090 μM). In vivo, AZD8835 showed pharmacodynamic modulation of AKT phosphorylation and near complete inhibition of tumour growth (93% tumour growth inhibition) in a murine H1047R PI3Kalpha mutated SKOV-3 xenograft tumour model after chronic oral administration at 25 mg/kg b.i.d. AZD8835, is currently in phase I clinical trials.

Chemical Structure

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AZD8835
CAS# 1620576-64-8
Product data Instruction

Theoretical Analysis

MedKoo Cat#: 206479
Name: AZD8835
CAS#: 1620576-64-8
Chemical Formula: C22H31N9O3
Exact Mass: 469.25
Molecular Weight: 469.550
Elemental Analysis: C, 56.28; H, 6.65; N, 26.85; O, 10.22

Price and Availability

Size Price Availability Quantity
10mg USD 150 Ready to ship
25mg USD 250 Ready to ship
50mg USD 450 Ready to ship
100mg USD 750 Ready to ship
200mg USD 1250 Ready to ship
500mg USD 1950 Ready to ship
1g USD 2850 2 Weeks
2g USD 3850 2 Weeks
5g USD 6950 2 Weeks
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Synonym: AZD-8835; AZD 8835; AZD8835.

IUPAC/Chemical Name: 1-(4-(5-(5-amino-6-(5-(tert-butyl)-1,3,4-oxadiazol-2-yl)pyrazin-2-yl)-1-ethyl-1H-1,2,4-triazol-3-yl)piperidin-1-yl)-3-hydroxypropan-1-one

InChi Key: ZGRDYKFVDCFJCZ-UHFFFAOYSA-N

InChi Code: InChI=1S/C22H31N9O3/c1-5-31-19(26-18(29-31)13-6-9-30(10-7-13)15(33)8-11-32)14-12-24-17(23)16(25-14)20-27-28-21(34-20)22(2,3)4/h12-13,32H,5-11H2,1-4H3,(H2,23,24)

SMILES Code: O=C(N1CCC(C2=NN(CC)C(C3=NC(C4=NN=C(C(C)(C)C)O4)=C(N)N=C3)=N2)CC1)CCO

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

More Info: At the enzyme level, AZD8835 is a potent mixed inhibitor of PI3Kα (IC50 0.0062 μM) and PI3Kδ (IC50 0.0057 μM), with selectivity against PI3Kβ (IC50 0.431 μM) and PI3Kγ (IC50 0.090 μM). AZD8835 is also a potent inhibitor of the commonly occurring PI3Kα mutants, PI3Kα - E545K (IC50 0.0060 μM) and PI3Kα - H1047R (IC50 0.0058 μM). In cell-based assays assessing the ability to inhibit AKT phosphorylation, AZD8835 was a potent inhibitor in cells sensitive to PI3Kα inhibition (IC50 0.057 μM in PIK3CA mutant human breast ductal carcinoma BT474 cell line) and in cells sensitive to PI3Kδ inhibition (IC50 0.049 μM in Jeko-1 B cell line), but not to cells sensitive to PI3Kβ inhibition (IC50 3.5 μM in PTEN null breast adenocarcinoma MDA-MB-468 cells) or to PI3Kγ inhibition (IC50 0.53 μM in monocytic RAW264 cell line).

Biological target: AZD8835 is an inhibitor of PI3Kα and PI3Kδ with IC50s of 6.2 and 5.7 nM, respectively.
In vitro activity: To identify the mechanisms responsible for AZD8835-mediated cytotoxicity, induction of apoptosis was analyzed using Annexin-V/PI staining in 2 sensitive (HBL-1 and TMD8) and 1 insensitive (BJAB) model. Predominantly in HBL-1 and less pronounced in TMD8 cells, a significant increase in apoptotic cells was observed, whereas no apoptosis was detectable in BJAB cells (Figure 4B). Analyses of proliferation after AZD8835 treatment using CFSE staining showed strongly decreased proliferation in HBL-1 and TMD8 but not in BJAB cells (Figure 4C). These results suggest that PI3Kα/δ inhibition results in induction of apoptosis and inhibition of proliferation in ABC DLBCLs. Reference: Blood. 2017 Jul 20;130(3):310-322. doi: 10.1182/blood-2016-12-758599. https://pubmed.ncbi.nlm.nih.gov/28202458/
In vivo activity: Initially, analyzing both proximal (pAKT) and downstream (pPRAS40, pS6) PI3K-pathway biomarkers in tumor tissue, this study demonstrated that pathway inhibition was both time and dose/exposure dependent (Fig. 3A). In parallel studies, this study observed glucose and insulin elevation as a transient pharmacologic response to AZD8835 in mice (Supplementary Fig. S2A and S2B), as also observed for other PI3K-inhibitors. Reference: Mol Cancer Ther. 2016 May;15(5):877-89. https://mct.aacrjournals.org/content/15/5/877.long

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMSO 43.0 91.58
DMSO:PBS (pH 7.2) (1:1) 0.5 1.06
DMF 16.0 34.08
Ethanol 2.0 4.26

Preparing Stock Solutions

The following data is based on the product molecular weight 469.55 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.

Recalculate based on batch purity %
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. Erdmann T, Klener P, Lynch JT, Grau M, Vočková P, Molinsky J, Tuskova D, Hudson K, Polanska UM, Grondine M, Mayo M, Dai B, Pfeifer M, Erdmann K, Schwammbach D, Zapukhlyak M, Staiger AM, Ott G, Berdel WE, Davies BR, Cruzalegui F, Trneny M, Lenz P, Barry ST, Lenz G. Sensitivity to PI3K and AKT inhibitors is mediated by divergent molecular mechanisms in subtypes of DLBCL. Blood. 2017 Jul 20;130(3):310-322. doi: 10.1182/blood-2016-12-758599. Epub 2017 Feb 15. PMID: 28202458. 2. Hudson K, Hancox UJ, Trigwell C, McEwen R, Polanska UM, Nikolaou M, Morentin Gutierrez P, Avivar-Valderas A, Delpuech O, Dudley P, Hanson L, Ellston R, Jones A, Cumberbatch M, Cosulich SC, Ward L, Cruzalegui F, Green S. Intermittent High-Dose Scheduling of AZD8835, a Novel Selective Inhibitor of PI3Kα and PI3Kδ, Demonstrates Treatment Strategies for PIK3CA-Dependent Breast Cancers. Mol Cancer Ther. 2016 May;15(5):877-89. doi: 10.1158/1535-7163.MCT-15-0687. Epub 2016 Feb 2. PMID: 26839307. 3. Carnevalli LS, Sinclair C, Taylor MA, Gutierrez PM, Langdon S, Coenen-Stass AML, Mooney L, Hughes A, Jarvis L, Staniszewska A, Crafter C, Sidders B, Hardaker E, Hudson K, Barry ST. PI3Kα/δ inhibition promotes anti-tumor immunity through direct enhancement of effector CD8+ T-cell activity. J Immunother Cancer. 2018 Dec 27;6(1):158. doi: 10.1186/s40425-018-0457-0. PMID: 30587236; PMCID: PMC6307194.
In vitro protocol: 1. Erdmann T, Klener P, Lynch JT, Grau M, Vočková P, Molinsky J, Tuskova D, Hudson K, Polanska UM, Grondine M, Mayo M, Dai B, Pfeifer M, Erdmann K, Schwammbach D, Zapukhlyak M, Staiger AM, Ott G, Berdel WE, Davies BR, Cruzalegui F, Trneny M, Lenz P, Barry ST, Lenz G. Sensitivity to PI3K and AKT inhibitors is mediated by divergent molecular mechanisms in subtypes of DLBCL. Blood. 2017 Jul 20;130(3):310-322. doi: 10.1182/blood-2016-12-758599. Epub 2017 Feb 15. PMID: 28202458. 2. Hudson K, Hancox UJ, Trigwell C, McEwen R, Polanska UM, Nikolaou M, Morentin Gutierrez P, Avivar-Valderas A, Delpuech O, Dudley P, Hanson L, Ellston R, Jones A, Cumberbatch M, Cosulich SC, Ward L, Cruzalegui F, Green S. Intermittent High-Dose Scheduling of AZD8835, a Novel Selective Inhibitor of PI3Kα and PI3Kδ, Demonstrates Treatment Strategies for PIK3CA-Dependent Breast Cancers. Mol Cancer Ther. 2016 May;15(5):877-89. doi: 10.1158/1535-7163.MCT-15-0687. Epub 2016 Feb 2. PMID: 26839307.
In vivo protocol: 1. Carnevalli LS, Sinclair C, Taylor MA, Gutierrez PM, Langdon S, Coenen-Stass AML, Mooney L, Hughes A, Jarvis L, Staniszewska A, Crafter C, Sidders B, Hardaker E, Hudson K, Barry ST. PI3Kα/δ inhibition promotes anti-tumor immunity through direct enhancement of effector CD8+ T-cell activity. J Immunother Cancer. 2018 Dec 27;6(1):158. doi: 10.1186/s40425-018-0457-0. PMID: 30587236; PMCID: PMC6307194. 2. Hudson K, Hancox UJ, Trigwell C, McEwen R, Polanska UM, Nikolaou M, Morentin Gutierrez P, Avivar-Valderas A, Delpuech O, Dudley P, Hanson L, Ellston R, Jones A, Cumberbatch M, Cosulich SC, Ward L, Cruzalegui F, Green S. Intermittent High-Dose Scheduling of AZD8835, a Novel Selective Inhibitor of PI3Kα and PI3Kδ, Demonstrates Treatment Strategies for PIK3CA-Dependent Breast Cancers. Mol Cancer Ther. 2016 May;15(5):877-89. doi: 10.1158/1535-7163.MCT-15-0687. Epub 2016 Feb 2. PMID: 26839307.

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