Background
AZD2461 is a novel PARP inhibitor with IC50 value of 5nM [1].
Poly (ADP-ribose) polymerase (PARP) is a family of proteins involved in a number of cellular processes involving mainly DNA repair and programmed cell death [1].
In SKBR-3 line and MCF-7 line, AZD2461 was cytotoxic and reduced numbers of viable cells in a concentration- and time-dependent manner. Also, through inhibiting PARP-1, AZD2461 increased MCF-7 cells and SKBR-3 cells in the G2 phase at the expense of proportions in the S- phase, respectively [2].
In order to investigate whether long-term dosing of AZD2461 would be capable of causing eradication or chronic suppression of KB1P tumors, which acquired Pgp-mediated resistance, we tested the response of KB1P tumors to the novel AZD2461. Both AZD2461 and olaparib completely inhibited the PARP activity for several hours, and 24 hours after treatment the amount of PAR returned to baseline levels. These data show that AZD2461 is a novel PARPi with potential to bypass Pgp-mediated resistance to olaparib. With short-term treatment, AZD2461 induces loss of 53BP1 expression in mice with KB1P tumors. Long-term AZD2461 treatment is well tolerated and doubled the median relapse-free survival [1].
Reference:
[1]. Jaspers JE, Kersbergen A, Boon U, et al. Loss of 53BP1 Causes PARP Inhibitor Resistance in Brca1-Mutated Mouse Mammary Tumors. Cancer Discov, 2013, 3(1): 68-81.
[2]. W?sierska GJ, Heinzl S. Interactions Between Ataxia Telangiectasia Mutated Kinase Inhibition, Poly(ADP-ribose) Polymerase-1 Inhibition and BRCA1 Status in Breast Cancer Cells. J Cancer Prev. 2014, 19(2): 125–136.
Protocol
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Cell experiment [1]:
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Cell lines
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human MCF-7 and SKBr-3 breast cancer cells
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Preparation method
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The solubility of this compound in DMSO is >16.35mg/mL. General tips for obtaining a higher concentration: Please warm the tube at 37℃ for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below -20℃ for several months.
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Reacting condition
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5-50 μM, 48 and 72h
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Applications
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In human MCF-7 and SKBr-3 breast cancer cells, AZD2461 was cytotoxic and reduced numbers of viable cells in a concentration- and time-dependent manner. PARP-1 inhibition by AZD2461 (10 μM for 48h) increased proportions of MCF-7 cells in the G2 phase and reduced cells in S-phase.
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Animal experiment [2]:
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Animal models
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mice with KB1P tumors
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Dosage form
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100 mg/kg p.o., 28 consecutive days or 100 consecutive days
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Application
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In mice with KB1P tumors, AZD2461 completely inhibited the PARP activity for several hours and the amount of PARP returned to baseline levels 24 hours after treatment. AZD2461 had lower affinity for Pgp than did olaparib. Mice treated with AZD2461 for 28 consecutive days showed increased survival. When treatment with AZD2461 for 100 consecutive days, 8 of 9 mice engrafted with fragments from 3 individual KB1P tumors did not develop refractory tumors within 300 days after treatment start. Long-term AZD2461 treatment was well tolerated and doubled the median relapse-free survival from 64 to 132 days.
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Other notes
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Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal.
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参考文献:
[1]. Wsierska GJ, Heinzl S. Interactions Between Ataxia Telangiectasia Mutated Kinase Inhibition, Poly(ADP-ribose) Polymerase-1 Inhibition and BRCA1 Status in Breast Cancer Cells. J Cancer Prev. 2014, 19(2): 125–136.
[2]. Jaspers JE, Kersbergen A, Boon U, et al. Loss of 53BP1 Causes PARP Inhibitor Resistance in Brca1-Mutated Mouse Mammary Tumors. Cancer Discov, 2013, 3(1): 68-81.
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