Rapid Apoptosis Induction by Dual Bcl-2/xL Inhibitor AZD4320 in Preclinical Hematologic Tumor Models

The process of apoptosis, which is a natural cellular mechanism, is controlled by the Bcl-2 family proteins that either promote or inhibit cell death. Cancer cells have developed ways to alter this balance, favoring survival and resistance to treatments. The Bcl-2 family proteins are often found amplified and overexpressed in various cancers, making them a target for BH3 mimetics, which have shown effectiveness in clinical trials, as seen with venetoclax for R/R CLL patients with 17p deletion.

A new compound, AZD4320, has been synthesized with a high affinity for Bcl-2 and Bcl-xL, akin to navitoclax, but with properties that allow for intravenous administration, potentially reducing the toxicities associated with oral navitoclax. AZD4320 acts as a genuine BH3 mimetic, disrupting the interaction between Bcl-2 and BH3-only proteins and requiring functional BAK and BAX for the apoptotic process. Kinetic studies on the Bcl-2-dependent B-ALL cell line RS4;11 showed a dose- and time-dependent increase in cleaved caspase-3 and a decrease in cell viability. AZD4320 was also effective against a range of hematological cancer cell lines with a median EC50 of 182nM, but solid tumor cell lines were less responsive. Compared to venetoclax, AZD4320 demonstrated greater sensitivity in hematological tumor cell lines and maintained potency in a venetoclax-resistant ABC-DLBCL cell line. In vivo studies with RS4;11 xenograft tumors showed tumor regression and induction of cleaved caspase-3 following a single dose of AZD4320.

The findings underscore the potential of a dual Bcl-2/xL inhibitor like AZD4320 as a foundational therapy for a variety of hematological cancers and as a means to overcome resistance to other BH3 mimetics and targeted treatments.