Antibody-Mediated Delivery of Chimeric BRD4 Degraders. Part 2: Improvement of In Vitro Antiproliferation Activity and In Vivo Antitumor Efficacy

Heterobifunctional
compounds that direct the ubiquitination of
intracellular proteins in a targeted manner via co-opted ubiquitin
ligases have enormous potential to transform the field of medicinal
chemistry. These chimeric molecules, often termed proteolysis-targeting
chimeras (PROTACs) in the chemical literature, enable the controlled
degradation of specific proteins via their direction to the cellular
proteasome. In this report, we describe the second phase of our research
focused on exploring antibody–drug conjugates (ADCs), which
incorporate BRD4-targeting chimeric degrader entities. We employ a
new BRD4-binding fragment in the construction of the chimeric ADC
payloads that is significantly more potent than the corresponding
entity utilized in our initial studies. The resulting BRD4-degrader
antibody conjugates exhibit potent and antigen-dependent BRD4 degradation
and antiproliferation activities in cell-based experiments. Multiple
ADCs bearing chimeric BRD4-degrader payloads also exhibit strong,
antigen-dependent antitumor efficacy in mouse xenograft assessments
that employ several different tumor models.