Diverse Amine-Acid Coupling Reactions Modulate the Potency of BRD4 PROTACs

18 December 2023, Version 1
This content is a preprint and has not undergone peer review at the time of posting.


Protein degradation with proteolysis targeting chimeras (PROTACs) has emerged as a powerful therapeutic strate-gy. PROTACs are heterobifunctional molecules consisting of a target-binding moiety, a linker and an E3 ligase-binding moiety that are commonly linked together using amide bonds. Although experimentally facile, this bond choice may impart sub-optimal drug properties to the overall PROTAC molecule. Here, we show that a suite of BRD4 PROTAC degraders were prepared via diverse amine-acid couplings beyond the amide bond, where the bromo-domain inhibitor JQ1 carboxylic acid was used as the acid and the E3-derived (Cereblon or Von Hippel Lindau) par-tial PROTACs served as the amine. Four new amine–acid coupling reactions were developed to generate the ester, ketone, alkane, or amine bond connection using miniaturized high-throughput experimentation (HTE). Subtle reac-tion condition effects in nickel and platinum catalyzed couplings on complex molecule substrates were uncovered, and the toolbox of linkage methods to synthesize heterobifunctional degraders was expanded. Calculated physico-chemical properties for these ten diversly linked PROTACs showed a wide range of lipophilicity, polar surface area, and hydrogen bonding characteristics. Ultimately, when these compounds were evaluated for BRD4 degradation, several of them showed improved efficacy. The ester, ketone, and alkane linked degraders outperform the classic amide-linked compound. This study highlights the impact that slight changes to the linkage between the protein of interest (POI) and E3 ligase binders can be used to modulate degradation and drug properties.


amine–acid couplings
protein degradation
high-throughput experimentation
reductive amination


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