AZD2461

Alias: AZD 2461; AZD-2461; AZD2461

Cat No.:V0310 Purity: ≥98%

COA Product Data Instructions for use SDS

AZD-2461 is a novel, selective and potent inhibitor of Poly (ADP-ribose) polymerase (PARP) with potential anticancer activity.

AZD2461 Chemical Structure CAS No.: 1174043-16-3
Product category: PARP

This product is for research use only, not for human use. We do not sell to patients.

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Citations by Top Journals: Nature, Cell, Science, etc.

Top Publications Citing lnvivochem Products

Nature 2021, 597(7874):119-125.

Cell 2020,183:1202-1218.e25.

Science Adv 2022: 8, eabm9427.

Nature 597, 119–125 (2021)

Cell Stem Cell 2020,26(6):845-861.e12.

Science Trans Med 2023,15(701):eadd7872.

STTT 2023,8(1):91.

Cell Reports 2023,42(4):112313

Science Trans Med 2023, 15: eadd7872.

Cancer Cell 2021,39(4):529-547.e7.

Cancer Discov 2022,12(4):1106-1127.

Immunity 2023,56(3):620-634.e11.

J Am Chem Soc 2022,144:21831-21836.

Cell 2020,183:1202-1218.e25.

Science Adv 2022:8,eabm9427.

Nature 2021,597(7874):119-125.

Cell 2020,183:1202-1218.e25.

PNAS Nexus 2022,1(3):pgac063.

ACS Nano 2023,17(10):9110-9125.

Biomaterial 2023 Sep16:302:122333.

Product Description
Bioactivity & Protocols
Physicochemical Properties
Solubility Data
Calculators
Clinical Trial Information
Biological Data

Product Description

AZD-2461 is a novel, selective and potent inhibitor of Poly (ADP-ribose) polymerase (PARP) with potential anticancer activity. In inhibits PARP1/2/3 with IC50 values of 5 nM, 2 nM and 200 nM, respectively. It was created as an improved form of olaparib and is a weak substrate of P-glycoprotein.

Biological Activity I Assay Protocols (From Reference)

Targets

PARP2 ( IC50 = 2 nM ); PARP1 ( IC50 = 5 nM ); PARP3 ( IC50 = 200 nM )

ln Vitro

In vitro activity: AZD-2461 is a novel and potent PARP inhibitor, with IC50 values for PARP1, PARP2, and PARP3 of 5 nM, 2 nM, and 200 nM, respectively. Human A459 cells demonstrate inhibitory activity of AZD-2461 (500 nM) against DNA single-strand break repair. The BRCA2-deficient mouse breast cancer line KB2P3.4 exhibits resistance to AZD-2461 as well as high levels of P-gp expression. The compound AZD-2461 exhibits cytotoxicity towards BT-20 cells (5-50 μM), augments the percentage of S- and G2-phase BT-20 cells (5-20 μM), and has a negligible impact on the cell cycle progression in SKBr-3 cells (5-20 μM)[2].

ln Vivo

AZD-2461 (10 mg/kg, p.o.) has minimal effect on mouse bone marrow cells while amplifying the antitumor activity of temozolomide in a mouse colorectal xenograft. Nevertheless, rat models do not exhibit the enhanced bone marrow tolerability of AZD-2461. After short-term treatment, mice with KB1P tumors are more likely to survive when given AZD-2461 (0.5% v/w HPMC, p.o.). Long-term treatment is well tolerated, but it cannot eradicate the tumor.

Enzyme Assay

AZD-2461 is a novel and potent inhibitor of PARP, with IC50s of 5 nM, 2 nM and 200 nM for PARP1, PARP2 and PARP3, respectively.

Cell Assay

The assay uses human primary breast cancer cell lines, BT-20 and SKBr-3. SKBr-3 cells are grown in DMEM medium containing 10% FCS and BT-20 in RPMI medium in a 5% CO₂ environment. The cells are treated with the PARP-1 inhibitors NU1025, AZD-2461, iniparib, olaparib, and rucaparib twenty-four hours after plating (at 60–70% confluence) for the durations shown in figures 1–7[2]. The concentrations of the inhibitors range from 50 to 200 μM, 5 to 50 μM, 1 to 10 μM, and 0.3 to 10 μM, respectively.

Animal Protocol

The size of the tumors is checked three times a week on mice starting two weeks after transplantation. When tumors grow to a size of about 200 mm³, all treatments begin. Unless otherwise specified, 28 days are allocated for the administration of AZD-2461 (100 mg/kg per os) and olaparib (50 mg/kg intraperitoneally). A new 28-day treatment cycle begins when the relapsing tumor reaches 100% of its original volume; if tumors do not shrink below 50% of their initial volume, treatment is continued for an additional 28 days. 10 mg/mL of AZD-2461 is obtained by diluting it with 0.5% w/v hydroxypropyl methylcellulose in deionized water.

References

[1]. The PARP Inhibitor AZD2461 Provides Insights into the Role of PARP3 Inhibition for Both Synthetic Lethality and Tolerability with Chemotherapy in Preclinical Models. Cancer Res . 2016 Oct 15;76(20):6084-6094.

[2]. Differential Potential of Pharmacological PARP Inhibitors for Inhibiting Cell Proliferation and Inducing Apoptosis in Human Breast Cancer Cells. J Cell Biochem. 2015 Dec;116(12):2824-39.

[3]. Loss of 53BP1 causes PARP inhibitor resistance in Brca1-mutated mouse mammary tumors. Cancer Discov. 2013 Jan;3(1):68-81.

These protocols are for reference only. InvivoChem does not independently validate these methods.

Physicochemical Properties

Molecular Formula

C22H22FN3O3

Molecular Weight

395.43

Exact Mass

395.16

Elemental Analysis

C, 66.82; H, 5.61; F, 4.80; N, 10.63; O, 12.14

CAS #

1174043-16-3

Related CAS #

1174043-16-3

Appearance

White solid powder

SMILES

COC1CCN(CC1)C(=O)C2=C(C=CC(=C2)CC3=NNC(=O)C4=CC=CC=C43)F

InChi Key

HYNBNUYQTQIHJK-UHFFFAOYSA-N

InChi Code

InChI=1S/C22H22FN3O3/c1-29-15-8-10-26(11-9-15)22(28)18-12-14(6-7-19(18)23)13-20-16-4-2-3-5-17(16)21(27)25-24-20/h2-7,12,15H,8-11,13H2,1H3,(H,25,27)

Chemical Name

4-[[4-fluoro-3-(4-methoxypiperidine-1-carbonyl)phenyl]methyl]-2H-phthalazin-1-one

Synonyms

AZD 2461; AZD-2461; AZD2461

HS Tariff Code

2934.99.9001

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)

Solubility Data

Solubility (In Vitro)

DMSO: ~10 mM

Water: <1 mg/mL

Ethanol: <1 mg/mL

Preparing Stock Solutions		1 mg	5 mg	10 mg
	1 mM	2.5289 mL	12.6445 mL	25.2889 mL
	5 mM	0.5058 mL	2.5289 mL	5.0578 mL
	10 mM	0.2529 mL	1.2644 mL	2.5289 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.

Calculator

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Molarity Calculator allows you to calculate the mass, volume, and/or concentration required for a solution, as detailed below:

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An example of molarity calculation using the molarity calculator is shown below:
What is the mass of compound required to make a 10 mM stock solution in 5 ml of DMSO given that the molecular weight of the compound is 350.26 g/mol?

Enter 350.26 in the Molecular Weight (MW) box
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The answer of 17.513 mg appears in the Mass box. In a similar way, you may calculate the volume and concentration.

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Dilution Calculator allows you to calculate how to dilute a stock solution of known concentrations. For example, you may Enter C1, C2 & V2 to calculate V1, as detailed below:

What volume of a given 10 mM stock solution is required to make 25 ml of a 25 μM solution?
Using the equation C1V1 = C2V2, where C1=10 mM, C2=25 μM, V2=25 ml and V1 is the unknown:

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The answer of 62.5 μL (0.1 ml) appears in the Volume (Start) box

Molecular formula

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Molecular Weight Calculator allows you to calculate the molar mass and elemental composition of a compound, as detailed below:

Note: Chemical formula is case sensitive: C12H18N3O4 c12h18n3o4
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Definitions of molecular mass, molecular weight, molar mass and molar weight:

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In vivo Formulation Calculator (Clear solution)

Step 1: Enter information below (Recommended: An additional animal to make allowance for loss during the experiment)

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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.

Note： (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.

Clinical Trial Information

NCT Number	Recruitment	interventions	Conditions	Sponsor/Collaborators	Start Date	Phases
NCT01247168	Completed	Drug: AZD2461	Refractory Solid Tumors Cancer Tumor	AstraZeneca	November 2010	Phase 1

Biological Data

AZD2461

AZD2461 has comparable effects on DNA single-strand break repair and efficacy as olaparibin vitro.

AZD2461

AZD2461 inhibits PARP3 to a lesser extent than olaparib, resulting in a lack of inhibition of nonhomologous end-joining repair in cancer cells.Cancer Res. 2016 Oct 15;76(20):6084-6094. Epub 2016 Aug 22.

AZD2461 overcomes P-gp–associated resistance to olaparib.Cancer Res. 2016 Oct 15;76(20):6084-6094. Epub 2016 Aug 22.

AZD2461

PARP3 levels are significantly higher in mouse but not rat or human bone marrow cells and, consistent with this, is a lack of differential bone marrow toxicity between AZD2461 and olaparib in rats.Cancer Res. 2016 Oct 15;76(20):6084-6094. Epub 2016 Aug 22.

AZD2461 is as effective as olaparib in potentiating the antitumor efficacy of temozolomide and shows lower impact on mouse bone marrow cells.Cancer Res. 2016 Oct 15;76(20):6084-6094. Epub 2016 Aug 22.

AZD2461

Comparison between the catalytic domains of PARP1 and PARP3. Sequence alignment of a portion of the catalytic domains of PARPs 1–3. Residues forming the “HYE triad” within the catalytic core (green arrows) and a PARP3-specific deletion (gray box) are shown.Cancer Res. 2016 Oct 15;76(20):6084-6094. Epub 2016 Aug 22.