New England Discovery Partners LLC

Protein asparagine (N)-glycosylation, which promotes the folding and trafficking of cell surface receptors, has not traditionally been viewed as a viable target in oncology due to the essential and non-redundant enzymatic activities required for glycan synthesis and transfer. However, in mammals, an exception is the presence of the oligosaccharyltransferase (OST) catalytic subunit paralogs, STT3A and STT3B. In this study, we investigate the biological activity of OST inhibitors and develop a strategy for selectively inhibiting N-glycosylation that is optimized for its downstream effects on the EGFR glycoprotein. Small molecules with improved pharmacokinetic properties and selective preferences for STT3A or STT3B were synthesized, characterized in vitro, and advanced to in vivo testing. The lead compound from this series, NGI-189, induces tumor regression or growth delay in patient-derived and TKI-resistant EGFR-mutant lung cancer xenografts without causing toxicity. Collectively, these findings suggest that bioavailable OST inhibitors can be developed as therapeutic agents for oncology.

Despite the promise of vastly expanding the druggable genome, rational design of RNA-targeting ligands remains challenging as it requires the rapid identification of hits and visualization of the resulting cocomplexes for guiding optimization. Here, we leveraged high-throughput screening, medicinal chemistry, and structural biology to identify a de novo splicing inhibitor against a large and highly folded fungal group I intron. High-resolution cryoEM structures of the intron in different liganded states not only reveal molecular interactions that rationalize experimental structure–activity relationship but also shed light on a unique strategy whereby RNA-associated metal ions and RNA conformation exhibit exceptional plasticity in response to small-molecule binding. This study reveals general principles that govern RNA–ligand recognition, the interplay between chemical bonding specificity, and dynamic responses within an RNA target.

We report the discovery of small molecules that target the RNA tertiary structure of self-splicing group II introns and display potent antifungal activity against yeasts, including the major public health threat Candida parapsilosis. High-throughput screening efforts against a yeast group II intron resulted in an inhibitor class which was then synthetically optimized for enhanced inhibitory activity and antifungal efficacy. The most highly refined compounds in this series display strong, gene-specific antifungal activity against C. parapsilosis. This work demonstrates the utility of combining advanced RNA screening methodologies with medicinal chemistry pipelines to identify high-affinity ligands targeting RNA tertiary structures with important roles in human health and disease.