dendrimer-conjugated Bcl-2/Bcl-XL inhibitor AZD0466

A drug-dendrimer conjugate composed of a B-cell lymphoma 2 (Bcl-2)/Bcl-XL inhibitor AZD4320 that is chemically conjugated to a proprietary 5-generation pegylated poly-lysine dendrimer via a hydrolytically labile linker, with potential pro-apoptotic and antineoplastic activities. Upon administration of AZD0466, AZD4320 is released through hydrolytic cleavage of the linker. AZD4320 is a Bcl2-homology domain 3 (BH3) mimetic that specifically binds to and inhibits the activity of the anti-apoptotic proteins Bcl-2 and Bcl-XL. This restores apoptotic processes and inhibits cell proliferation in Bcl-2/Bcl-XL-dependent tumor cells. Bcl-2 and Bcl-XL, proteins belonging to the Bcl-2 family that are overexpressed in many cancers, play an important role in the negative regulation of apoptosis. Their expression in tumors is associated with increased drug resistance and cancer cell survival. The conjugation of AZD 4320 to the dendrimer construct may allow extended release of the agent, which may improve efficacy and lower toxicity.