产品说明书

AZD-2461

Print
Chemical Structure| 1174043-16-3 同义名 : -
CAS号 : 1174043-16-3
货号 : A810897
分子式 : C22H22FN3O3
纯度 : 99%+
分子量 : 395.427
MDL号 : MFCD24386811
存储条件：

粉末 Inert atmosphere,2-8°C

液体 -20°C:3-6个月-80°C:12个月
溶解度 :

DMSO: 105 mg/mL(265.54 mM)，注意：DMSO长时间开封后，会吸水并导致溶解能力下降，请避免使用长期开封的DMSO
动物实验配方：

2% DMSO+40% PEG 300+2% Tween 80+water 5 mg/mL

生物活性
靶点

  • PARP
描述 The inhibition of poly (ADP-ribose) polymerases (PARP) has been used as a therapeutic strategy for homologous recombination–deficient tumors. AZD2461 is a potent inhibitor of both PARP1 and PARP2 with IC50 values of 5 nM and 2 nM, respectively. In human A549 cells, 500 nM AZD2461 inhibited poly (ADP-ribose) polymers formation following the treatment with 10 mM hydrogen peroxide. AZD2461 at 500 nM also augmented the anti-proliferative effect of the DNA-damaging alkylating agent MMS in HeLa cells. In colorectal cancer cell line HCT-15, the activity of AZD2461 alone or in combination with the P-gp inhibitor verapamil showed the IC50 values of 6.4 and 5.7 μM, respectively[4]. In vivo, a single p.o. administration of 100 mg/kg AZD2461 completely inhibited the PARP activity for a couple of hours and then returned to baseline level 24 hours after the treatment. Compared to olaparib-treated animals, consecutive oral administration of AZD2461 (100 mg/kg) for 28 days increased the survival rate in mice with KB1P tumors, but all mice eventually developed refractory tumors. When AZD2461 treatment was extended to 100 consecutive days, 8 out of 9 mice showed no relapsing tumors within 300 days after the treatment began[5].
作用机制 AZD2461 is an orally available compound with lower affinity to P-glycoprotein. It selectively binds to PARP, inhibiting PARP-mediated DNA repair[4].
实验方案
1mg 5mg 10mg

1 mM

5 mM

10 mM

2.53mL

0.51mL

0.25mL

12.64mL

2.53mL

1.26mL

25.29mL

5.06mL

2.53mL
参考文献

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

[2]Oplustil O'Connor L, Rulten SL, et al. 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. Epub 2016 Aug 22.

[3]Henneman L, van Miltenburg MH, et al. Selective resistance to the PARP inhibitor olaparib in a mouse model for BRCA1-deficient metaplastic breast cancer. Proc Natl Acad Sci U S A. 2015 Jul 7;112(27):8409-14.

[4]Oplustil O'Connor L, Rulten SL, Cranston AN, Odedra R, Brown H, Jaspers JE, Jones L, Knights C, Evers B, Ting A, Bradbury RH, Pajic M, Rottenberg S, Jonkers J, Rudge D, Martin NM, Caldecott KW, Lau A, O'Connor MJ. 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.

[5]Jaspers JE, Kersbergen A, Boon U, Sol W, van Deemter L, Zander SA, Drost R, Wientjens E, Ji J, Aly A, Doroshow JH, Cranston A, Martin NM, Lau A, O'Connor MJ, Ganesan S, Borst P, Jonkers J, Rottenberg S. Loss of 53BP1 causes PARP inhibitor resistance in Brca1-mutated mouse mammary tumors. Cancer Discov. 2013 Jan;3(1):68-81.