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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.
| Targets |
PARP2 ( IC50 = 2 nM ); PARP1 ( IC50 = 5 nM ); PARP3 ( IC50 = 200 nM )
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| ln Vitro |
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| 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.
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| 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.
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| Additional Infomation |
PARP Inhibitor AZD2461 is an orally bioavailable inhibitor of the nuclear enzyme poly(ADP-ribose) polymerase (PARP) with potential antineoplastic activity. PARP inhibitor AZD2461 selectively binds to PARP and prevents PARP-mediated DNA repair of single strand DNA breaks via the base-excision repair pathway. This enhances the accumulation of DNA strand breaks and promotes genomic instability and eventually leads to apoptosis. PARP catalyzes post-translational ADP-ribosylation of nuclear proteins that signal and recruit other proteins to repair damaged DNA and is activated by single-strand DNA breaks.
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| Molecular Formula |
C22H22FN3O3
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| Molecular Weight |
395.43
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| Exact Mass |
395.164
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| Elemental Analysis |
C, 66.82; H, 5.61; F, 4.80; N, 10.63; O, 12.14
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| CAS # |
1174043-16-3
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| Related CAS # |
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| PubChem CID |
44199317
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| Appearance |
White solid powder
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| Density |
1.3±0.1 g/cm3
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| Index of Refraction |
1.640
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| LogP |
0.53
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
5
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| Rotatable Bond Count |
4
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| Heavy Atom Count |
29
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| Complexity |
647
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| Defined Atom Stereocenter Count |
0
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| SMILES |
FC1C([H])=C([H])C(C([H])([H])C2C3=C([H])C([H])=C([H])C([H])=C3C(N([H])N=2)=O)=C([H])C=1C(N1C([H])([H])C([H])([H])C([H])(C([H])([H])C1([H])[H])OC([H])([H])[H])=O
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| InChi Key |
HYNBNUYQTQIHJK-UHFFFAOYSA-N
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| 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)
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| Chemical Name |
4-[[4-fluoro-3-(4-methoxypiperidine-1-carbonyl)phenyl]methyl]-2H-phthalazin-1-one
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| Synonyms |
AZD 2461; AZD-2461; AZD2461
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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 |
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| 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) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (6.32 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 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL 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 2: ≥ 2.5 mg/mL (6.32 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 25.0 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. View More
Solubility in Formulation 3: ≥ 2.5 mg/mL (6.32 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| 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.
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 | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT01247168 | Completed | Drug: AZD2461 | Refractory Solid Tumors Cancer Tumor |
AstraZeneca | November 2010 | Phase 1 |
AZD2461 has comparable effects on DNA single-strand break repair and efficacy as olaparibin vitro.
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. |
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AZD2461 overcomes P-gp–associated resistance to olaparib.Cancer Res. 2016 Oct 15;76(20):6084-6094. Epub 2016 Aug 22. |
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. |
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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. |
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