Modular cytokine receptor-targeting chimeras for targeted degradation of cell surface and extracellular proteins.

Targeted degradation of cell surface and extracellular proteins via lysosomal delivery is an important means to modulate extracellular biology. However, these approaches have limitations due to lack of modularity, ease of development, restricted tissue targeting and applicability to both cell surface and extracellular proteins. We describe a lysosomal degradation strategy, termed cytokine receptor-targeting chimeras (KineTACs), that addresses these limitations.

Ras-mutant cancers are sensitive to small molecule inhibition of V-type ATPases in mice.

Mutations in Ras family proteins are implicated in 33% of human cancers, but direct pharmacological inhibition of Ras mutants remains challenging. As an alternative to direct inhibition, we screened for sensitivities in Ras-mutant cells and discovered 249C as a Ras-mutant selective cytotoxic agent with nanomolar potency against a spectrum of Ras-mutant cancers. 249C binds to vacuolar (V)-ATPase with nanomolar affinity and inhibits its activity, preventing lysosomal acidification and inhibiting autophagy and macropinocytosis pathways that several Ras-driven cancers rely on for survival.

Roadmap for Optimizing and Broadening Antibody-Based PROTACs for Degradation of Cell Surface Proteins.

Targeted protein degradation is a promising therapeutic strategy capable of overcoming the limitations of traditional occupancy-based inhibitors. By ablating all of the associated functions of a protein at once, the event-driven pharmacology of degrader technologies has recently enabled the targeting of proteins that have been historically deemed "undruggable". Most degradation strategies utilize the ubiquitin-proteasome system to mediate intracellular target degradation and are thus limited to targeting proteins with cytoplasmic domains.

Examining Gender Imbalance in Chemistry Authorship.

Despite decades of progress toward a more equitable society, gender representation in the sciences continues to be heavily skewed toward men. We were interested in gender representation in chemistry through the lens of scientific publishing. Publications are a central academic currency and are critical for funding, recruiting, and promotion in academia.

Biotin as a Reactive Handle to Selectively Label Proteins and DNA with Small Molecules.

Biotin is a common functional handle for bioconjugation to proteins and DNA, but its uses are limited to protein-containing conjugation partners such as streptavidin and derivatives thereof. Recently, oxaziridine reagents were developed that selectively conjugate the thioether of methionines on the surface of proteins, a method termed redox-activated chemical tagging (ReACT). These reagents generate sulfimide linkages that range in stability depending on the solvent accessibility and substitutions on the oxaziridine.

Development of Antibody-Based PROTACs for the Degradation of the Cell-Surface Immune Checkpoint Protein PD-L1.

Targeted protein degradation has emerged as a new paradigm to manipulate cellular proteostasis. Proteolysis-targeting chimeras (PROTACs) are bifunctional small molecules that recruit an E3 ligase to a target protein of interest, promoting its ubiquitination and subsequent degradation. Here, we report the development of antibody-based PROTACs (AbTACs), fully recombinant bispecific antibodies that recruit membrane-bound E3 ligases for the degradation of cell-surface proteins.