Modulating the Potency of BRD4 PROTACs at the Systems Level with Amine-Acid Coupling Reactions

Abstract

Protein degradation using proteolysis targeting chimeras (PROTACs) represents a promising therapeutic strategy. PROTACs are heterobifunctional molecules that consist of a target-binding moiety and an E3 ligase binding moiety, connected by a linker. These fragments are frequently united via amide bonds. While straightforward to synthesize, amides may impart suboptimal drug properties to the overall molecule. From a systems level perspective, we envisioned that the potency of PROTACs could be modulated through selection of reaction conditions─wherein different catalysts produce distinct linkers from the same two building blocks. We present a suite of BRD4 PROTAC degraders prepared via four new amine–acid coupling reactions alongside the classic amide coupling. Our findings reveal that variations in reaction conditions affect the physicochemical properties of PROTACs, resulting in a spectrum of properties. Notably, several new PROTACs demonstrated enhanced BRD4 degradation efficacy compared to those employing amide linkers, emphasizing the potential of systems chemistry as a therapeutic optimization strategy.