Our lab works broadly across the field of targeting post-translational modification, from small molecular drug discovery to antibody-degrader conjugates. Here I will introduce our work discovering an exceptionally potent ADC payload with an unprecedented mode of action targeting protein lipidation, and a new approach to unlock proximity-driven pharmacology through Site-specific Ligand-Induced Proximity (SLIP), enabling systematic identification of actionable sites on potential effector proteins, opening new opportunities for future proximity-induced pharmacology (PIP)-based drug discovery. 

The Nomura research group is focused on reimagining druggability using chemoproteomic platforms to develop transformative medicines. One of the greatest challenges that we face in discovering new disease therapies is that most proteins are considered “undruggable,” in that most proteins do not possess known binding pockets or “ligandable hotspots” that small molecules can bind to modulate protein function. Our research group addresses this challenge by advancing and applying chemoproteomic platforms to discover and pharmacologically target unique and novel ligandable hotspots for disease therapy.

Electrophilic libraries often contain thousands of members, resulting in hundreds of TMT plexes to profile entire libraries. In this talk, I will i) highlight how TMT multiplexing and sample pooling can be combined, ii) address issues with increased DMSO concentrations, iii) discuss strategies for deconvolution, and iv) provide an example of "2D pooling" where deconvolution is built into the sample design.

Gynecology remains one of the least-funded areas of human health. The NIH has launched “Complement-ARIE” to bolster mergers of systems biology and microphysiological systems for regulatory purposes. Examples of engineering living patient avatars will provide specific technical insights for integrating clinical and molecular/cellular phenotyping and designing in vitro models for validating targets and mechanism of action, especially for chronic inflammatory diseases like endometriosis.

The recognition that condensate dysfunction underlies a broad spectrum of diseases has opened new opportunities to modulate high-value targets. We have leveraged emerging insights into condensate biology to build a comprehensive drug-discovery platform that expands the mechanistic and target space of small-molecule therapeutics. Our condensate-modifying compounds (c-mods) enable selective modulation of undruggable targets, such as MYC and ß-catenin, and demonstrate robust disease-modifying activity in vitro and in vivo.

Understanding protein dynamics is critical for drug discovery against challenging targets. We describe an integrated platform that combines all-atom physics-based simulations with biophysical data, including HDX-MS and crystallography, to model biologically relevant protein motions and thermodynamics. We use this approach to enable mechanism-driven design strategies to advance our therapeutic pipeline of novel orally bioavailable molecules against clinically validated inflammation and immunology targets.