A5049482291- Protein Degradation and Inhibitors
- Ubiquitin and proteasome pathways
- Cancer-related Molecular Pathways
- Genomics and Chromatin Dynamics
- Epigenetics and DNA Methylation
- Peptidase Inhibition and Analysis
- Click Chemistry and Applications
- Cancer-related gene regulation
- Histone Deacetylase Inhibitors Research
- RNA modifications and cancer
- Electron and X-Ray Spectroscopy Techniques
- HIV Research and Treatment
- CRISPR and Genetic Engineering
- Pluripotent Stem Cells Research
- interferon and immune responses
- Polymer Nanocomposite Synthesis and Irradiation
- Nanofabrication and Lithography Techniques
- Genetics and Neurodevelopmental Disorders
- Immune cells in cancer
- Microtubule and mitosis dynamics
- Photonic and Optical Devices
- Immune Cell Function and Interaction
- Analytical Chemistry and Sensors
- Semiconductor materials and devices
Friedrich Miescher Institute
2020-2024
Dana-Farber Cancer Institute
2023
University of Basel
2020-2023
Transcription factors (TFs) regulate gene expression through chromatin where nucleosomes restrict DNA access. To study how TFs bind nucleosome-occupied motifs, we focused on the reprogramming OCT4 and SOX2 in mouse embryonic stem cells. We determined TF engagement throughout a nucleosome at base-pair resolution vitro, enabling structure determination by cryo-electron microscopy two preferred positions. Depending motif location, differentially distort nucleosomal DNA. At one position,...
Abstract Molecular glue degraders are an effective therapeutic modality, but their design principles not well understood. Recently, several unexpectedly diverse compounds were reported to deplete cyclin K by linking CDK12–cyclin the DDB1–CUL4–RBX1 E3 ligase. Here, investigate how chemically dissimilar small molecules trigger degradation, we evaluated 91 candidate in structural, biophysical and cellular studies reveal all acquire activity via simultaneous CDK12 binding engagement of DDB1...
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 possibility that local environment can contextualize regulation. Here, we show epigenetic characteristics closed chromatin, such as DNA methylation, do not influence across genome. Instead, ability open activate its target genes is locally restricted by cofactor Trim24. Trim24 binds both unmethylated 3...
Proteolysis targeting chimeras (PROTACs) are heterobifunctional molecules that induce the degradation of proteins interest (POIs) via ubiquitin-proteasome pathway by recruiting E3 ligases to form a ternary complex with POI. In this study, we rationally designed and synthesized PROTACs αβ-tubulin heterodimer, building block microtubules (MTs) essential for numerous cellular functions represent important therapeutic targets in cancer neurodegenerative diseases. Maytansinol, known...
Small molecules that induce protein interactions hold tremendous potential as new medicines, probes for molecular pathways, and tools agriculture. Explosive growth of targeted degradation (TPD) drug development has spurred renewed interest in proximity-inducing especially Molecular Glue Degraders (MGDs). These compounds catalyze destruction disease-causing proteins by reshaping surfaces promoting cooperative binding between ubiquitylating enzymes target proteins. MGD discovery pre-defined...
Targeted covalent inhibition (TCI) and targeted protein degradation (TPD) have proven effective in pharmacologically addressing formerly 'undruggable' targets. Integration of both methodologies has resulted the development electrophilic degraders where recruitment a suitable E3 ubiquitin ligase is achieved through formation bond with cysteine nucleophile. Expanding scope requires electrophiles tempered reactivity that enable selective reduce cross-reactivity other cellular nucleophiles. In...
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 rational design using gluing moieties. By appending a chemical moiety to several small molecule inhibitors, successfully transformed them into degraders, obviat-ing need...
Abstract 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 possibility that provides context-dependence for regulation. Here, we show ability open activate its target genes is indeed locally restricted by cofactor Trim24. Trim24 binds both unmethylated lysine 4 H3, thereby preferentially locating those reside closed chromatin, while it deterred from...
Illuminating the path to degrading troublesome proteins.