AZD2281 (Olaparib)

Biological Activity

AZD 2281 (Olaparib, KU-0059436) is a  novel, potent orally active PARP (poly ADP-ribose polymerase) inhibitorwith IC50 of 5 and 1 nM for PARP-1and PARP-2  respectively. AZD 2281 (Olaparib, KU-0059436) acts as an inhibitor of the enzyme Poly ADP ribose polymerase (PARP) and is one of the first PARP inhibitors.It induces cancer specific synthetic lethality in homologous recombination repair defective cells, including BRCA-deficient tumors. Olaparib is an autophagy and mitophagy activator.

Product Citations

• 

  Journal of Cancer. 2024 Jan;15(3):699-713.

  Radiosensitization of Osteosarcoma Cells Using the PARP Inhibitor Olaparib Combined with X-rays or Carbon Ions
  AZD2281 (Olaparib) purchased from AbMole

• 

  Sci Adv. 2022 May 13;8(19):eabn1229.

  Translesion DNA synthesis mediates acquired resistance to olaparib plus temozolomide in small cell lung cancer
  AZD2281 (Olaparib) purchased from AbMole

• 

  Free Radic Biol Med. 2022 Jan;178:174-188.

  DNA damage response proteins synergistically affect the cancer prognosis and resistance
  AZD2281 (Olaparib) purchased from AbMole

• 

  Radiat Oncol. 2022 Aug 19;17(1):144.

  Ku70 affects the frequency of chromosome translocation in human lymphocytes after radiation and T-cell acute lymphoblastic leukemia
  AZD2281 (Olaparib) purchased from AbMole

• 

  BMC Biol. 2021 May 20;19(1):108.

  Very long intergenic non-coding (vlinc) RNAs directly regulate multiple genes in cis and trans
  AZD2281 (Olaparib) purchased from AbMole

• 

  Int J Biol Sci. 2021 Jan 31;17(3):689-701.

  Preclinical evaluation of radiation therapy of BRCA1-associated mammary tumors using a mouse model
  AZD2281 (Olaparib) purchased from AbMole

• 

  Cell. 2019 Jun 13;177(7):1903-1914.e14.

  Visualizing Engrafted Human Cancer and Therapy Responses in Immunodeficient Zebrafish.
  AZD2281 (Olaparib) purchased from AbMole

• 

  Clin Cancer Res. 2019 Mar 1;25(5):1664-1675.

  The Ewing Family of Tumors Relies on BCL-2 and BCL-XL to Escape PARP Inhibitor Toxicity.
  AZD2281 (Olaparib) purchased from AbMole

• 

  Int J Biol Sci. 2018 Oct 3;14(13):1769-1781.

  Inhibition of AKT suppresses the initiation and progression of BRCA1-associated mammary tumors.
  AZD2281 (Olaparib) purchased from AbMole

Customer Product Validations & Biological Datas

	Source	Int J Biol Sci (2018 Oct). Figure 5. Olaparib (Abmole Bioscience, Houston, USA)
	Method	IP
	Cell Lines	mice
	Concentrations	100 mg/kg
	Incubation Time	-
	Results	The overall RTVs (treated vs. non-treated tumors) for mice bearing Brca1-mutant tumor allografts were 60.8% and 62.6% for mice treated with MK-2206 and olaparib, respectively.

	Source	Int J Biol Sci (2018 Oct). Figure 4. Olaparib (Abmole Bioscience, Houston, USA)
	Method	IP
	Cell Lines	mice
	Concentrations	100 mg/kg
	Incubation Time	-
	Results	In mice co-treated with olaparib and MK-2206, tumor volume was only increased ~1.8-fold at this same time, indicating that these agents exerted a additive effect on tumor growth.

	Source	Int J Oncol (2015). Figure 4. AZD2281
	Method	apoptosis assay
	Cell Lines	HCC‑1428 cells
	Concentrations	2 μM
	Incubation Time	4 day
	Results	Inhibition of autophagy by knocking down ATG5 also partially inhibited AZD2281-induced apoptosis, suggesting that autophagy contributes to AZD2281-induced cell death in BRCA mutated breast cancer cells.

	Source	Int J Oncol (2015). Figure 1. AZD2281
	Method	Transmission electron microscopy
	Cell Lines	BRCA1 or BRCA2 mutant breast cancer cell lines
	Concentrations	2 μM
	Incubation Time	4 day
	Results	The growth inhibition effect of AZD2281 was significantly higher in the BRCA wild-type cell lines with BRCA1 allelic loss than in the BRCA wild-type cell line without BRCA1 allelic loss.

Protocol (for reference only)

Cell Experiment
Cell lines	SW620 colorectal cell line
Preparation method	Potentiation of MMS Cytotoxicity by 47 Determined by the Use of Sulforhodamine B Cell Growth Assays. SW620 cells were seeded in 96-well plates and were left to attach overnight. Cells were preincubated with vehicle control (DMSO) or with a single concentration of KU-0059436 (1, 3, 10, 30, 100 or 300 nM) for 1 h before the addition of increasing concentrations of MMS. Cells were incubated in the presence of each drug combination for 4 days before cell growth was quantified by the use of an SRB assay.44 Data were calculated from triplicate wells as the mean percentage of cell growth relative to KU-0059436-only wells, and (SE and IC50 were calculated by the use of XL-FIT 4 software. SW620 cells showed <24% growth inhibition (>76% cell growth) when only KU-0059436 was used at concentrations below 300 nM (data not shown).
Concentrations	1, 3, 10, 100 and 300 nM
Incubation time	4 days

Animal Experiment
Animal models	mouse bearing SW620 xenografted tumors
Formulation	methylcellulose/PBS
Dosages	10 mg/kg once daily for 5 consecutive days
Administration	orally

Chemical Information

Molecular Weight	434.46
Formula	C24H23FN4O3
CAS Number	763113-22-0
Solubility (25°C)	DMSO 90 mg/mL DMF 45 mg/mL
Storage	Powder          -20°C   3 years ;  4°C   2 years In solvent       -80°C   6 months ;  -20°C   1 month

Conversion of different model animals based on BSA (PMID: 27057123)

Species	Mouse	Rat	Rabbit	Guinea pig	Hamster	Dog
Weight (kg)	0.02	0.15	1.8	0.4	0.08	10
Body Surface Area (m2)	0.007	0.025	0.15	0.05	0.02	0.5
Km factor	3	6	12	8	5	20

Animal A (mg/kg) = Animal B (mg/kg) multiplied by	Animal B Km
	Animal A Km

For example, to modify the dose of Compound A used for a mouse (20 mg/kg) to a dose based on the BSA for a rat, multiply 20 mg/kg by the K_m factor for a mouse and then divide by the K_m factor for a rat. This calculation results in a rat equivalent dose for Compound A of 10 mg/kg.

References

[1] Bajrami et al. EMBO Mol Med. Synthetic lethality of PARP and NAMPT inhibition in triple-negative breast cancer cells.

[2] Itamochi et al. Int J Clin Oncol. Clinical trials and future potential of targeted therapy for ovarian cancer.

[3] Ibrahim et al. Cancer Discov. PI3K inhibition impairs BRCA1/2 expression and sensitizes BRCA proficient triple negative breast cancer to PARP inhibition.

[4] Daemen et al. Breast Cancer Res Treat. Cross-platform pathway-based analysis identifies markers of response to the PARP inhibitor olaparib.

[5] Marchetti et al. Expert Opin Investig Drugs. Olaparib , PARP1 inhibitor in ovarian cancer.

[6] Keith A Menear, et al. J Med Chem . 4-[3-(4-cyclopropanecarbonylpiperazine-1-carbonyl)-4-fluorobenzyl]-2H-phthalazin-1-one: a novel bioavailable inhibitor of poly(ADP-ribose) polymerase-1