We determined that LZK (encoded by MAP3K13) is a therapeutic target in HNSCC and showed that inhibition with small molecule inhibitors decreases the viability of HNSCC cells with amplified MAP3K13. A drug-resistant mutant of LZK blocks decreases in cell viability due to LZK inhibition, indicating on-target activity by two separate small molecules. Inhibition of LZK catalytic activity suppressed tumor growth in HNSCC PDX models with amplified MAP3K13. We designed proteolysis-targeting chimeras (PROTACs) and demonstrate that our lead PROTAC promotes LZK degradation and suppresses expression of GOF p53 and c-MYC, leading to impaired viability of HNSCC.

Following the success of PROTACs laying the framework for modulation of protein levels as a therapeutic strategy, the field of protein degradation has witnessed an unprecedented expansion in new drug modalities. This talk will discuss strategies to discover and develop these next generation molecules, translating basic research innovation into therapeutically active compounds.

Through a retrospective analysis of the pharmacokinetic profiles of a large set of PROTAC molecules, we have derived PROTAC design constraints on physicochemical properties associated with higher probability of oral bioavailability. This data was further used to train a machine-learning model to predict oral-absorption performance to further prospective design efforts of orally bioavailable molecules.

The design of molecular glue degraders (MGD) has been challenging and the discovery of novel MGD/neosubstrate pairs has relied primarily on different screening strategies. In this talk, I will discuss our multipronged screening approaches (phenotypic, targeted, and proteome-wide) against a molecular glue library based on cereblon binders and the discovery of novel degrader-neosubstrate pairs.

We introduce a NanoBRET-powered high-throughput platform that lights up molecular glue activity in live cells. By capturing real-time E3 ligase–substrate interactions, this assay enables rapid, scalable discovery of glue degraders with high sensitivity and physiological relevance, offering a powerful tool to unlock new therapeutic mechanisms and expand the degradable proteome.

The Slabicki Laboratory investigates the mechanistic basis of protein degradation by leveraging functional genomics and reprogramming the ubiquitin-proteasome system. Using advanced screening and biochemical approaches, we elucidate target-ligase interactions to accelerate therapeutic discovery for diseases lacking effective treatments. In our current work, we characterize neosubstrate recognition by CRBN, revealing how auxiliary degron interactions define and expand target scope and selectivity, enabling the rational design of more selective protein degraders.

Our proprietary platform, RaPPIDS, facilitates the rapid production of degrader molecules and effective evaluation of targeted protein degradation. The high productivity of this platform enables us to discover not only novel E3 ligase binders by taking phenotypic-first approach but also well-optimized degraders with suitable DMPK profile. In this talk, I will share some case studies from our ongoing research programs.