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Olaparib (AZD2281, Ku-0059436) (Synonyms: AZD 2281, Ku0059436)

Catalog No.GC17580

Un inhibidor de PARP

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Olaparib (AZD2281, Ku-0059436) Chemical Structure

Cas No.: 763113-22-0

Tamaño Precio Disponibilidad Cantidad
10mM (in 1mL DMSO)
41,00 $
Disponible
10mg
36,00 $
Disponible
100mg
112,00 $
Disponible
500mg
473,00 $
Disponible

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Sample solution is provided at 25 µL, 10mM.

Product has been cited by 2 publications

Product Documents

Quality Control & SDS

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Protocol

Kinase experiment [1]:

Preparation Method

Measured PARP-2 activity inhibition by using a variation of the PARP-1 assay in which PARP-2 protein (recombinant) was bound down by a PARP-2 specific antibody in a 96-well white-walled plate. PARP-2 activity was measured following 3H NAD+ DNA additions. After washing, scintillant was added to measure 3H-incorporated ribosylations. For tankyrase-1,HIS-tagged recombinant TANK-1 protein was incubated with biotinylated NAD+. Alpha beads were added to bind the HIS and biotin tags to create a proximity signal, whereas the inhibition of TANK-1 activity was directly proportional to the loss of this signal.

Reaction Conditions

5 different concentrations of Olaparib (AZD2281, Ku-0059436)(in the range around the predetermined IC50 value)

Applications

Olaparib (AZD2281, KU0059436) is a selective PARP1/2 inhibitor with IC50 of 5 nM/1 nM, and its effect on PARP1/2 is 300 times higher than that of Tankyrase-1.

Cell experiment [2]:

Cell lines

Breast cancer MDA-MB-463 and HCC1937 cell

Preparation Method

Cells were seeded in six-well plates and left overnight Vector control (DMSO) or increasing concentrations of Olaparib (AZD2281, Ku-0059436)(up to 4 μM) were added to the cells and, depending on the cell type, the mixture was left for 7-14 days before counting surviving colonies

Reaction Conditions

4 μM Olaparib (AZD2281, Ku-0059436)for 7-14 days

Applications

Brca1-deficient cell lines were highly sensitive to PARP inhibition by Olaparib (AZD2281, Ku-0059436)

Animal experiment [3]:

Animal models

Mice(The SW620 cell tumor model)

Preparation Method

Animals carrying SW620 xenograft tumors were treated with Olaparib (AZD2281, Ku-0059436) (10mg/kg) in combination with TMZ(50mg/kg) once daily for 5 days

Dosage form

10mg/kg Olaparib (AZD2281, Ku-0059436) for 5 days( oral administration)

Applications

Considerable inhibition of tumor volumes as compared with that of the TMZ alone group was observed for the TMZ plus Olaparib (AZD2281, Ku-0059436) combination. This equated to over 80% tumor growth inhibition throughout the entire terminal phase of the study between TMZ treatment and the combination.

References:

[1]. Menear KA, Adcock C,et,al. 4-[3-(4-cyclopropanecarbonylpiperazine-1-carbonyl)-4-fluorobenzyl]-2H-phthalazin-1-one: a novel bioavailable inhibitor of poly(ADP-ribose) polymerase-1. J Med Chem. 2008 Oct 23;51(20):6581-91. doi: 10.1021/jm8001263. Epub 2008 Sep 19. PMID: 18800822.

Background

Olaparib (AZD2281, Ku-0059436) es un inhibidor potente y selectivo de PARP que específicamente se dirige a PARP1 y PARP2 (IC 50 = 5 nM y 1 nM, respectivamente). Es un activador de la autofagia y mitofagia.

Las líneas celulares deficientes en Brca1 fueron altamente sensibles a la inhibición de PARP por Olaparib (AZD2281, Ku-0059436) [1] . Olaparib (AZD2281, Ku-0059436) mejora la radioterapia, no solo al inhibir la reparación del ADN sino también al cambiar la hemodinámica vascular tumoral en el carcinoma de pulmón no microcítico (NSCLC). En las células Calu-6 y A549 irradiadas, Olaparib (AZD2281, Ku-0059436) mejoró los efectos citotóxicos de la radiación (relación de mejora del sensibilizador al 10% de supervivencia = 1.5 y 1.3), y las roturas dobles del ADN persistieron durante al menos 24 horas después del tratamiento[2]. Las células cancerosas endometriales endometrioides deficientes en PTEN no responden al inhibidor de PARP Olaparib (AZD2281, Ku-0059436) solas, sino que muestran una mayor sensibilidad a la inhibición compuesta con el inhibidor PI3K BKM120, como se evidencia por una reducción en el crecimiento clonogénico celular y desintegración esférica tridimensional (3D)[4].

Se observó una considerable inhibición del volumen tumoral en comparación con el grupo tratado solo con TMZ para la combinación de TMZ más Olaparib (AZD2281, Ku-0059436). Esto equivalió a una inhibición del crecimiento tumoral de más del 80% durante toda la fase terminal del estudio entre el tratamiento con TMZ y la combinación. El inhibidor PARP AZD2281 (olaparib) mostró efectos sinérgicos con cisplatino de manera dependiente de la dosis. El tratamiento combinado con cisplatino y AZD2281 inhibió significativamente el crecimiento tumoral xenoinjertado en comparación con el tratamiento único de cisplatino u Olaparib (AZD2281, Ku-0059436). El tratamiento de ratones portadores de tumor con AZD2281 inhibió el crecimiento tumoral sin signos de toxicidad, lo que resultó en un aumento significativo en la supervivencia. Sin embargo, el tratamiento a largo plazo con Olaparib (AZD2281, Ku-0059436) en este modelo dio como resultado el desarrollo de resistencia al fármaco. Se detectaron daños en ADN indicados por los focos γH2AX completamente indetectables en folículos primordiales animales control pero se observaron en un 10% de ovocitos sobrevivientes del folículo primordial tratados solo con Olaparib (AZD2281, Ku-0059436). Cuando se exploró la posible combinación del PAPRi Olaparib (AZD2281, Ku-0059436) junto a células T CAR dirigidas contra EGFRvIII (806-28Z CAR) en modelos murinos inmunocompetentes de cáncer de mama, la administración de Olaparib (AZD2281, Ku-0059436) podría mejorar significativamente la eficacia de las células T CAR 806-28Z in vivo. Olaparib (AZD2281, Ku-0059436) podría suprimir la migración celular supresora derivada del mieloide y promover la supervivencia de las células T CD8+ en el tejido tumoral.

References:
[1]: Menear KA, Adcock C,et,al. 4-[3-(4-cyclopropanecarbonylpiperazine-1-carbonyl)-4-fluorobenzyl]-2H-phthalazin-1-one: a novel bioavailable inhibitor of poly(ADP-ribose) polymerase-1. J Med Chem. 2008 Oct 23;51(20):6581-91. doi: 10.1021/jm8001263. Epub 2008 Sep 19. PMID: 18800822.
[2]: Senra JM, Telfer BA, et,al. Inhibition of PARP-1 by olaparib (AZD2281) increases the radiosensitivity of a lung tumor xenograft. Mol Cancer Ther. 2011 Oct;10(10):1949-58. doi: 10.1158/1535-7163.MCT-11-0278. Epub 2011 Aug 8. PMID: 21825006; PMCID: PMC3192032.
[3]: Yasukawa M, Fujihara H, et,al. Synergetic Effects of PARP Inhibitor AZD2281 and Cisplatin in Oral Squamous Cell Carcinoma in Vitro and in Vivo. Int J Mol Sci. 2016 Feb 24;17(3):272. doi: 10.3390/ijms17030272. PMID: 26927065; PMCID: PMC4813136.
[4]: Bian X, Gao J, et,al. PTEN deficiency sensitizes endometrioid endometrial cancer to compound PARP-PI3K inhibition but not PARP inhibition as monotherapy. Oncogene. 2018 Jan 18;37(3):341-351. doi: 10.1038/onc.2017.326. Epub 2017 Sep 25. PMID: 28945226; PMCID: PMC5799770.
[5]: Rottenberg S, Jaspers JE, et,al. High sensitivity of BRCA1-deficient mammary tumors to the PARP inhibitor AZD2281 alone and in combination with platinum drugs. Proc Natl Acad Sci U S A. 2008 Nov 4;105(44):17079-84. doi: 10.1073/pnas.0806092105. Epub 2008 Oct 29. PMID: 18971340; PMCID: PMC2579381.
[6]: Sun R, Luo H, et,al.Olaparib Suppresses MDSC Recruitment via SDF1α/CXCR4 Axis to Improve the Anti-tumor Efficacy of CAR-T Cells on Breast Cancer in Mice. Mol Ther. 2021 Jan 6;29(1):60-74. doi: 10.1016/j.ymthe.2020.09.034. Epub 2020 Sep 26. PMID: 33010818; PMCID: PMC7791086.
[7]: Winship AL, Griffiths M, et,al. The PARP inhibitor, olaparib, depletes the ovarian reserve in mice: implications for fertility preservation. Hum Reprod. 2020 Aug 1;35(8):1864-1874. doi: 10.1093/humrep/deaa128. PMID: 32604417.

Chemical Properties

Cas No. 763113-22-0 SDF
Sinónimos AZD 2281, Ku0059436
Chemical Name 4-[[3-[4-(cyclopropanecarbonyl)piperazine-1-carbonyl]-4-fluorophenyl]methyl]-2H-phthalazin-1-one
Canonical SMILES C1CC1C(=O)N2CCN(CC2)C(=O)C3=C(C=CC(=C3)CC4=NNC(=O)C5=CC=CC=C54)F
Formula C24H23FN4O3 M.Wt 434.46
Solubility ≥ 21.72 mg/mL in DMSO Storage Store at -20°C
General tips Please select the appropriate solvent to prepare the stock solution according to the solubility of the product in different solvents; once the solution is prepared, please store it in separate packages to avoid product failure caused by repeated freezing and thawing.Storage method and period of the stock solution: When stored at -80°C, please use it within 6 months; when stored at -20°C, please use it within 1 month.
To increase solubility, heat the tube to 37°C and then oscillate in an ultrasonic bath for some time.
Shipping Condition Evaluation sample solution: shipped with blue ice. All other sizes available: with RT, or with Blue Ice upon request.

Complete Stock Solution Preparation Table

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1 mg 5 mg 10 mg
1 mM 2.3017 mL 11.5085 mL 23.0171 mL
5 mM 0.4603 mL 2.3017 mL 4.6034 mL
10 mM 0.2302 mL 1.1509 mL 2.3017 mL
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