Modulating\nthe Potency of BRD4 PROTACs at the Systems\nLevel with Amine-Acid Coupling\nReactions

Protein degradation using proteolysis\ntargeting chimeras\n(PROTACs)\nrepresents a promising therapeutic strategy. PROTACs are heterobifunctional\nmolecules that consist of a target-binding moiety and an E3 ligase\nbinding moiety, connected by a linker. These fragments are frequently\nunited via amide bonds. While straightforward to synthesize, amides\nmay impart suboptimal drug properties to the overall molecule. From\na systems level perspective, we envisioned that the potency of PROTACs\ncould be modulated through selection of reaction conditionswherein\ndifferent catalysts produce distinct linkers from the same two building\nblocks. We present a suite of BRD4 PROTAC degraders prepared via four\nnew amine–acid coupling reactions alongside the classic amide\ncoupling. Our findings reveal that variations in reaction conditions\naffect the physicochemical properties of PROTACs, resulting in a spectrum\nof properties. Notably, several new PROTACs demonstrated enhanced\nBRD4 degradation efficacy compared to those employing amide linkers,\nemphasizing the potential of systems chemistry as a therapeutic optimization\nstrategy.