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].
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