Słabicki Laboratory

Overview

The Słabicki laboratory is dedicated to expanding the druggable proteome by employing functional genomics and targeted protein degradation. We harness the body’s own waste disposal machinery, especially the E3 ligases that can flag malfunctioning proteins for disposal, to develop new treatments. Leveraging our extensive expertise in functional genomics, cell biology, bioinformatics, molecular biology, chemical biology and biochemistry, we reprogram the ubiquitin-proteasome system to identify and characterize novel therapeutic modalities. Our work enhances our fundamental understanding of biology and enables the creation of new treatments for diseases that currently lack therapeutic options.

Research Summary

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.

The Słabicki 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.

Our recent research led to the identification of the kinase inhibitor CR8 as a molecular glue degrader. Unlike previous examples of degraders, CR8 induces an interaction between a target and a substrate adaptor in the absence of a traditional substrate receptor. CR8 induces a neo-interaction between the CDK12-cyclin K complex and DDB1, inducing the ubiquitination and subsequent degradation of cyclin K (Słabicki M, Kozicka Z, Petzold G, et al., Nature. 2020). We also identified the intricate mechanism through which the small molecule BI-3802 promotes the polymerization of the oncogenic transcription factor BCL6, leading to enhanced ubiquitination by the E3 ligase SIAH1 and subsequent proteasomal degradation (Słabicki M, Yoon H, Koeppel J, et al., Nature. 2020). Both findings revealed novel mechanisms by which proteins can be degraded, expanding the repertoire of therapeutic opportunities for otherwise difficult-to-target proteins.

Building on the small molecule-induced polymerization of BCL6, our team has developed a drug-induced, reversible polymerization switch. By fusing BCL6-BTB domain to the epidermal growth factor receptor (EGFR), we were able to activate downstream signaling pathways and promote cellular proliferation, when the polymerization-inducing drug was present, even in the absence of epidermal growth factor (EGF), (Nitsch, L. et al. Cell Rep Methods, 2022). We also defined how the human E3 ligase RNF185 influences the stability of the SARS-CoV-2 Envelope protein (Zou, C., et al., iScience, 2023). Currently, our team is engaged in a project that aims to broaden the scope of human zinc finger degrons targeted by glutaramide analogs via CRBN.

The Słabicki laboratory’s future research will use high throughput chemical genomic approaches to systematically dissect the protein homeostasis machinery for clinically relevant targets. We will further elucidate the mechanisms governing protein-ligase interactions, establish comprehensive E3-ligase target maps, and expand the array of targets amenable to small molecule-mediated degradation. Our ultimate objective is to advance the development of precision-based therapeutic interventions, particularly in the field of oncology, while simultaneously establishing a comprehensive framework for identifying E3 ligases for unique protein targets.

Select Publications

Park PMC, Park J, Brown J, Hunkeler M, Roy Burman SS, Donovan KA, Yoon H, Nowak RP, Słabicki M, Ebert BL, Fischer ES. Polymerization of ZBTB transcription factors regulates chromatin occupancy. Mol Cell. 2024 Jul 11;84(13):2511-2524.e8.

Zou C, Yoon H, Park PMC, Patten JJ, Pellman J, Carreiro J, Tsai JM, Li YD, Roy Burman SS, Donovan KA, Gasser J, Sperling AS, Nowak RP, Fischer ES, Davey RA, Ebert BL, Słabicki M.^# The human E3 ligase RNF185 is a regulator of the SARS-CoV-2 envelope protein. iScience. 2023 May 19;26(5):106601.

Nitsch L, Jensen P, Yoon H, Koeppel J, Burman SSR, Fischer ES, Scholl C, Fröhling S, Słabicki M.^# BTB-BCL6 dimers as building blocks for reversible drug-induced protein oligomerization. Cell Rep Methods. 2022 Apr 13;2(4):100193.

Słabicki M*, Yoon H*, Koeppel J*, Nitsch L, Burman SSR, Di Genua C, Donovan KA, Sperling AS, Hunkeler M, Tsai JM, Sharma R, Guirguis A, Zou C, Chudasama P, Gasser JA, Miller PG, Scholl C, Fröhling S, Nowak RP, Fischer ES, Ebert BL. Small molecule-induced polymerization triggers degradation of BCL6. Nature. 2020 Nov 18.

Słabicki M*, Kozicka Z*, Petzold G*, Li Y, Manojkumar M, Bunker R, Donovan KA, Sievers QL, Koeppel J, Suchyta D, Sperling AS, Fink EC, Gasser JA, Wang LR, Corsello SM, Sellar RS, Jan M, Gillingham D, Scholl C, Fröhling S, Golub TR, Fischer ES, Thomä NH, Ebert BL The CDK inhibitor CR8 acts as a molecular glue degrader depleting cyclin K. Nature. 2020. Sep;585(7824):293-297.

*Co-first author
#Corresponding author

Our Researchers

Mikołaj Słabicki, PhD
Principal Investigator

• Molly Fraser
• Marek M. Nagiec, PhD
• Jesse Pellman
• Abby Perschon