Mikolaj Slabicki, PhD

Massachusetts General Hospital

Academic Titles

Assistant Professor, Medicine, Harvard Medical School

Research Program Affiliation

Member, Developmental Therapeutics

Member, Cancer Cell Biology

Research Abstract

Targeted protein degradation (TPD) is an exciting and novel pharmacological modality in which the ubiquitin proteasome system (UPS) is reprogrammed to induce depletion of targets that are often otherwise undruggable. Unlike traditional occupancy-based inhibitors, TPD utilizes event-based pharmacology, degrading multiple target protein molecules with a single drug molecule, possibly enhancing clinical effectiveness. Two main classes of degraders exist. First, monovalent molecular glue degraders - such as the clinically-used thalidomide, lenalidomide, and pomalidomide - were discovered to work by binding to an E3 ligase and degrading neo-substrates. Second, PROteolysis TArgeting Chimeras (PROTACs) are rationally designed bi-functional molecules that contain two moieties: one that binds to a target protein and one that engages an E3 ubiquitin ligase.

My laboratory will advance both foundational knowledge and therapeutic innovation in protein degradation by developing new approaches and establishing new workflows. For example, we have extensively optimized a generalizable fluorescent reporter and flow cytometry-based CRISPR screening method to identify genes that regulate the post-translational stability of any protein of interest. By elucidating the mechanisms governing target-ligase interactions, we aim to expedite the discovery and optimization of promising drug candidates.