Jennifer D. Venable

Reactions that form ethers are used broadly for pharmaceutical, fragrance, materials, and agrichemical applications. We report here an amine-acid etherification reaction that proceeds via a facile amine-halogen exchange and an ester-selective reduction. The method employs free aliphatic amines and carboxylic acids to form C(sp3)–O ether bonds directly. This method allows a diverse range of readily available alkyl amines and acids to be transformed into synthetically valuable alkyl ethers, which are challenging to access by conventional methods. The etherification reaction proves to be suitable for late-stage diversification and repurposing of building blocks to expand chemical space. Additionally, this methodology provides a straightforward approach for accessing medicinally relevant α-deuterated ethers. Reaction development was facilitated by high-throughput experimentation and computational and experimental mechanistic studies. Furthermore, the deamination strategy can be extended to other nucleo-philes, enabling the synthesis of phenolic ethers and a range of halide products. Our reaction protocol exhibited selective reduction of esters in the presence of amides, supported by both experimental and computational studies. Overall, this work establishes a versatile amine-halogen exchange as a platform for constructing structurally diverse ethers from abundant feedstocks.

Solute carrier (SLC) transporters govern the selective transport of diverse molecules across cell membranes, controlling fundamental metabolic and cellular processes. Despite genetic evidence implicating SLC transporters in a variety of human diseases, this family of proteins represents an underexplored target class for therapeutic drug discovery. Here, we discovered a selective potentiator of SLC39A8, a metal transporter associated with inflammatory bowel disease, schizophrenia, and cardiovascular and metabolic disorders. We conducted a drug repurposing screen, identifying efavirenz as a potentiator of manganese and cadmium uptake by SLC39A8 and subsequently generated structure-activity relationships to guide design of analogs. Computational pocket identification methodology and molecular dynamic simulations revealed a ligandable, cryptic pocket that, together with functional mutagenesis, indicated direct target engagement and allosteric modulation. Our findings demonstrate how the combination of experimental data and computational tools represents a powerful synergy that can enhance scientific outcomes. This integrated approach allowed for iterative feedback where insights from experiments informed the model refinements and computational predictions guided future experimental designs. Furthermore, our data established that SLC39A8 transporter activity can be increased pharmacologically, potentially opening avenues for SLC transporter drug discovery.

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.

Target 2035, an international federation of biomedical scientists from the public and private sectors, is leveraging ‘open’ principles to develop a pharmacological tool for every human protein.