Herein, we report a general and scalable continuous flow metallaphotoredox amidine arylation protocol that efficiently couples diverse (hetero)aryl halides and amidines under mild open-air conditions. Mechanistic studies revealed the pivotal role of an in situ generated triazine cocatalyst, which acts as the quencher in the photocatalytic cycle via an underexplored oxidative quenching pathway. Its strategic use as a cocatalyst enabled faster kinetics, broader nucleophile scope, including sulfonamides and amines, and the use of alternative solvents. These insights unlock a previously challenging reactivity, enhancing both the synthetic utility and sustainability of our nickel/photoredox cross-coupling.

A novel series of inhibitors of the interaction of IL-17A with its cognate receptor has been discovered using DNA-encoded library (DEL) technology. The lead compound (JNJ627, Compound 1) of the series occupies the interior interface of the IL-17A homodimer and disables receptor binding. The mechanism of action involves allosteric disruption of the IL-17A quaternary structure to prevent adoption of the receptor-binding conformation, rather than direct orthosteric inhibition at the receptor-binding site. Molecules of this series exhibit remarkably slow on-rate kinetics and potent inhibition of IL-17A signaling in human primary cells.

First-time disclosures session at ACS Fall 2025 reveals diverse candidates for treating sickle cell disease, heart failure, cancer, and more.

STIP1 homology and U-box containing protein 1 (STUB1), also known as the C-terminus of Hsc70-interacting protein (CHIP), is an E3 ligase that plays a crucial role in removal of misfolded proteins via Hsc70. A DEL screen was run against CHIP to identify small-molecule binders. Two hits were identified that were confirmed by biochemical and biophysical techniques, including 2D NMR. X-ray crystal structures were obtained, which revealed binding to the peptide binding site. Fragment-based deconstruction indicated that hit 2 was a suitable starting point for optimization. During the optimization, an unexpected rearrangement of an oxadiazole from an array hit led to the exploration of an amide vector. This resulted in the discovery of compound 5, which is the most potent small-molecule ligand for CHIP identified to date and a suitable starting point for further optimization into a tool molecule or PROTAC warhead.

Cyclopropanes play an important role in drug discovery, and synthetic access to variedly substituted systems is an ongoing challenge for chemistry teams. A variety of scalable synthetic routes were developed and optimized for the construction of 1,2-trans-disubstituted cyclopropyl esters. The use of a stable cyclopropyl trifluoroborate provided a path for the rapid exploration of heteroaryl substituent diversity. Two asymmetric approaches were subsequently enabled as viable alternatives. Our first approach led to the development of a novel sulfoximine-driven Johnson–Corey–Chaykovsky reaction of menthyl acrylates and is the first example of this chemistry for the enantio- and diastereostereoselective construction of trans-cyclopropanes. Ultimately, a scalable process route was fashioned through the optimization of an efficient ring opening/intramolecular C–O phosphate transfer and displacement cascade that builds the trans-cyclopropyl ester from a chiral epoxide with excellent stereocontrol.

Evaluating synthetic accessibility of in silico molecules is an integral component of the drug discovery process. While the application of machine learning models to predict whether small molecules are easy or hard to synthesize has gained attention recently, predetermined thresholds and data set imbalances present challenges for these binary classification approaches. In this study, we introduce a novel multiclass fold-ensembled classification approach to predict the minimum number of steps needed to synthesize a small molecule. By ensembling the base models trained on multiple stratified subsampled folds, this approach effectively mitigates the impact of class imbalance through probability aggregation or voting aggregation strategies. Additionally, we propose fuzzy evaluation metrics that account for practical tolerances in predictions, providing a more flexible and realistic assessment of model performance. Through experimentation on two reaction benchmark data sets, we demonstrate the effectiveness of our model in a multiclass synthetic accessibility prediction task and the superiority of our proposed method over six existing models in binary synthetic accessibility prediction tasks.

The recent global COVID-19 pandemic has highlighted treatments for coronavirus infection as an unmet medical need. The main protease (M^pro) has been an important target for the development of SARS-CoV-2 direct-acting antivirals. Nirmatrelvir as a covalent M^pro inhibitor was the first such approved therapy. Although M^pro inhibitors of various chemical classes have been reported, they are generally less active against nirmatrelvir-resistant variants and have limited pan-coronavirus potential, presenting a significant human health risk upon future outbreaks. We here present a novel approach and utilized DNA-encoded chemical library screening to identify a noncovalent M^pro inhibitor, which demonstrated a distinct binding mode to nirmatrelvir. A macrocyclization strategy designed to lock the active conformation resulted in a lactone with significantly improved antiviral activity. Further optimization led to a potent lactam, which demonstrated exceptional potency against nirmatrelvir-resistant variants as well as against a panel of viral main proteases from other coronaviruses.

Target class-focused drug discovery has a strong track record in pharmaceutical research, yet public domain data indicate that many members of protein families remain unliganded. Here we present a systematic approach to scale up the discovery and characterization of small molecule ligands for the WD40 repeat (WDR) protein family. We developed a comprehensive suite of protocols for protein production, crystallography, and biophysical, biochemical, and cellular assays. A pilot hit-finding campaign using DNA-encoded chemical library selection followed by machine learning (DEL-ML) to predict ligands from virtual libraries yielded first-in-class, drug-like ligands for 7 of the 16 WDR domains screened, thus demonstrating the broader ligandability of WDRs. This study establishes a template for evaluation of protein family wide ligandability and provides an extensive resource of WDR protein biochemical and chemical tools, knowledge, and protocols to discover potential therapeutics for this highly disease-relevant, but underexplored target class.

Amino acids are vital motifs in the domain of biochemistry, serving as the foundational unit for peptides and proteins, while also holding a crucial function in many biological processes. Due to their bifunctional character, they have been also used for combinatorial chemistry purposes, such as the preparation of DNA-encoded chemical libraries. We developed a practical synthesis for α-heteroaryl-α-amino acids starting from an array of small heteroaromatic halides. The reaction sequence utilizes a photochemically enhanced Negishi cross-coupling as a key step, followed by oximation and reduction. The prepared amino esters were validated for on-DNA reactivity via a reverse amidation–hydrolysis–reverse amidation protocol.

Bfl-1 is over-expressed in both hematological and solid tumors, inhibitors of Bfl-1 are therefore highly desirable.  A DNA-encoded chemical library (DEL) screen against Bfl-1 identified the first known reversible-covalent small molecule ligand for Bfl-1. The binding was validated through biophysical and biochemical techniques, which confirmed the reversible-covalent mechanism of action and pointed to binding through Cys55. This represented the first identification of a cyano-acrylamide reversible-covalent compound from a DEL screen and highlights further opportunities for covalent drug discovery through DEL screening. A 10-fold improvement in potency was achieved through a systematic SAR exploration of the hit. The more potent analogue compound 13 was successfully co-crystallized in Bfl-1 revealing the binding-mode and providing further evidence of a covalent interaction with Cys55.