Zuzanna Kozicka

• Doctor of Philosophy
• Bridging Postdoctoral Researcher at Friedrich Miescher Institute

Targeted protein degradation (TPD) is an emerging therapeutic approach for the selective elimination of disease-related proteins. While molecular glue degraders exhibit drug-like properties, their discovery has traditionally been serendipitous and often requires post-hoc rationalization. In this study, we demonstrate the rational design of molecula...

Targeted covalent inhibition (TCI) and targeted protein degradation (TPD) have proven effective in pharmacologically addressing formerly 'undruggable' targets. Integration of both methodologies has resulted in the development of electrophilic degraders where recruitment of a suitable E3 ubiquitin ligase is achieved through formation of a covalent b...

Small molecules that induce protein interactions hold tremendous potential as new medicines, as probes for molecular pathways, and as tools for agriculture. Explosive growth of targeted protein degradation (TPD) drug development has spurred renewed interest in proximity-inducing molecules and especially Molecular Glue Degraders (MGDs). These compou...

Illuminating the path to degrading troublesome proteins

Molecular glue degraders are an effective therapeutic modality, but their design principles are not well understood. Recently, several unexpectedly diverse compounds were reported to deplete cyclin K by linking CDK12–cyclin K to the DDB1–CUL4–RBX1 E3 ligase. Here, to investigate how chemically dissimilar small molecules trigger cyclin K degradation...

The genomic binding sites of the transcription factor (TF) and tumor suppressor p53 are unusually diverse with regard to their chromatin features, including histone modifications, raising the possibility that the local chromatin environment can contextualize p53 regulation. Here, we show that epigenetic characteristics of closed chromatin, such as...

The genomic binding sites of the transcription factor (TF) and tumour suppressor p53 are unusually diverse in regards to their chromatin features, including histone modifications, opening the possibility that chromatin provides context-dependence for p53 regulation. Here, we show that the ability of p53 to open chromatin and activate its target gen...

Molecular glue degraders are small, drug-like compounds that induce interactions between an E3 ubiquitin ligase and a target, which result in ubiquitination and subsequent degradation of the recruited protein. In recent years, serendipitous discoveries revealed that some preclinical and clinical compounds already work as molecular glue degraders, w...

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

The DNA sensor cGAS initiates innate immune responses following microbial infection, cellular stress, and cancer1. Upon activation by double-stranded DNA, cytosolic cGAS produces 2'3' cyclic GMP-AMP and triggers inflammatory cytokine and type I interferon (IFN) induction2-7. cGAS is also present inside the cell nucleus replete with genomic DNA8, wh...

Targeted protein degradation is a new therapeutic modality based on drugs that destabilize proteins by inducing their proximity to E3 ubiquitin ligases. Of particular interest are molecular glues that can degrade otherwise unligandable proteins by orchestrating direct interactions between target and ligase. However, their discovery has so far been...

Molecular glue compounds induce protein–protein interactions that, in the context of a ubiquitin ligase, lead to protein degradation1. Unlike traditional enzyme inhibitors, these molecular glue degraders act substoichiometrically to catalyse the rapid depletion of previously inaccessible targets2. They are clinically effective and highly sought-aft...

Molecular glue compounds induce protein-protein interactions that, in the context of a ubiquitin ligase, lead to protein degradation1. Unlike traditional enzyme inhibitors, these molecular glue degraders act substoichiometrically to catalyse the rapid depletion of previously inaccessible targets2. They are clinically effective and highly sought-aft...

Engaging the nucleosome Cell identity is defined by gene expression patterns that are established through the binding of specific transcription factors. However, nucleosomal units limit access of transcription factors to specific DNA motifs within the mammalian genome. To study how transcription factors bind such chromatinized, nucleosome-embedded...

PCSK9 heightens LDL cholesterol levels by chaperoning the liver LDL receptor to lysosomes for degradation. In this issue of Cell Chemical Biology, Petrilli et al. (2020) identify novel PCSK9 ligands and convert them into a proof-of-concept degrader, offering a unique way to modulate this key protein-protein interaction.