AZD2461

Biological Activity

AZD2461 is a novel PARP inhibitor with low affinity for Pgp than Olaparib. AZD2461 has an 80-fold increased Mdr1b expression on Olaparib-resistant KB1P tumor T6-28, without inhibition of Pgp. AZD2461 induces loss of 53BP1 expression in mice with KB1P tumors with short-term treatment. Long-term AZD2461 treatment is well tolerated and doubled the median relapse-free survival. Importantly, PARPi resistance was minimized by long-term treatment with the novel PARP inhibitor AZD2461, which is a poor P-glycoprotein substrate.

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

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 resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 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 resveratrol of 11.2 mg/kg.

Chemical Information

References

Loss of 53BP1 causes PARP inhibitor resistance in Brca1-mutated mouse mammary tumors.
Jaspers JE,et al. Cancer Discov. 2013 Jan;3(1):68-81. PMID: 23103855.