Andrea Testa
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View article: Phase-separated droplets swim to their dissolution
Phase-separated droplets swim to their dissolution Open
Biological macromolecules can condense into liquid domains. In cells, these condensates form membraneless organelles that can organize chemical reactions. However, little is known about the physical consequences of chemical activity in and…
View article: The 17<sup>th</sup> EFMC Short Course on Medicinal Chemistry on Small Molecule Protein Degraders
The 17<sup>th</sup> EFMC Short Course on Medicinal Chemistry on Small Molecule Protein Degraders Open
The 17 th EFMC Short Course on Medicinal Chemistry took place April 23–26, 2023 in Oegstgeest, near Leiden in the Netherlands. It covered for the first time the exciting topic of Targeted Protein Degradation (full title: Small Molecule Pro…
View article: Surface Passivation Method for the Super-repellence of Aqueous Macromolecular Condensates
Surface Passivation Method for the Super-repellence of Aqueous Macromolecular Condensates Open
Solutions of macromolecules can undergo liquid-liquid phase separation to form droplets with ultralow surface tension. Droplets with such low surface tension wet and spread over common surfaces such as test tubes and microscope slides, com…
View article: Structure-based design of a phosphotyrosine-masked covalent ligand targeting the E3 ligase SOCS2
Structure-based design of a phosphotyrosine-masked covalent ligand targeting the E3 ligase SOCS2 Open
The Src homology 2 (SH2) domain recognises phosphotyrosine (pY) post translational modifications in partner proteins to trigger downstream signalling. Drug discovery efforts targeting the SH2 domains have long been stymied by the poor drug…
View article: Phase-Separated Droplets Swim to Their Dissolution
Phase-Separated Droplets Swim to Their Dissolution Open
Biological macromolecules can condense into liquid domains. In cells, these condensates form membraneless organelles that can organize chemical reactions1,2. However, little is known about the physical consequences of chemical activity in …
View article: Surface Passivation Method for Super-repellence of Aqueous Macromolecular Condensates
Surface Passivation Method for Super-repellence of Aqueous Macromolecular Condensates Open
Solutions of macromolecules can undergo liquid-liquid phase separation to form droplets with ultra-low surface tension. Droplets with such low surface tension wet and spread over common surfaces such as test tubes and microscope slides, co…
View article: Targeted protein degradation via intramolecular bivalent glues
Targeted protein degradation via intramolecular bivalent glues Open
Targeted protein degradation is a pharmacological modality based on the induced proximity of an E3 ubiquitin ligase and a target protein to promote target ubiquitination and proteasomal degradation. This has been achieved either via bifunc…
View article: Functional E3 ligase hotspots and resistance mechanisms to small-molecule degraders
Functional E3 ligase hotspots and resistance mechanisms to small-molecule degraders Open
Targeted protein degradation is a novel pharmacology established by drugs that recruit target proteins to E3 ubiquitin ligases. Based on the structure of the degrader and the target, different E3 interfaces are critically involved, thus fo…
View article: Structure-based design of a phosphotyrosine-masked covalent ligand targeting the E3 ligase SOCS2
Structure-based design of a phosphotyrosine-masked covalent ligand targeting the E3 ligase SOCS2 Open
The Src homology 2 (SH2) domain is present in many proteins that bind to phosphotyrosine (pY) post translational modifications in partner proteins to trigger downstream signalling. Since pY-driven protein-protein interactions can sustain d…
View article: Charting functional E3 ligase hotspots and resistance mechanisms to small-molecule degraders
Charting functional E3 ligase hotspots and resistance mechanisms to small-molecule degraders Open
Targeted protein degradation is a new pharmacologic paradigm established by drugs that recruit target proteins to E3 ubiquitin ligases via a ternary ligase-degrader-target complex. Based on the structure of the degrader and the neosubstrat…
View article: The bromodomain and extra-terminal domain degrader MZ1 exhibits preclinical anti-tumoral activity in diffuse large B-cell lymphoma of the activated B cell-like type
The bromodomain and extra-terminal domain degrader MZ1 exhibits preclinical anti-tumoral activity in diffuse large B-cell lymphoma of the activated B cell-like type Open
Aim: Bromodomain and extra-terminal domain (BET) proteins are epigenetic readers that play a fundamental role in transcription regulation. Preclinical and early clinical evidence sustain BET targeting as an anti-cancer approach. BET degrad…
View article: Trivalent PROTACs enhance protein degradation via combined avidity and cooperativity
Trivalent PROTACs enhance protein degradation via combined avidity and cooperativity Open
Bivalent PROTACs work drive protein degradation by simultaneously binding a target protein and an E3 ligase and forming a productive ternary complex. We hypothesized that increasing binding valency within a PROTAC could enhanced degradatio…
View article: Trivalent PROTACs enhance protein degradation via combined avidity and cooperativity
Trivalent PROTACs enhance protein degradation via combined avidity and cooperativity Open
Bivalent PROTACs work drive protein degradation by simultaneously binding a target protein and an E3 ligase and forming a productive ternary complex. We hypothesized that increasing binding valency within a PROTAC could enhanced degradatio…
View article: Development of BromoTag: A “Bump-and-Hole”–PROTAC System to Induce Potent, Rapid, and Selective Degradation of Tagged Target Proteins
Development of BromoTag: A “Bump-and-Hole”–PROTAC System to Induce Potent, Rapid, and Selective Degradation of Tagged Target Proteins Open
Small-molecule-induced protein depletion technologies, also called inducible degrons, allow degradation of genetically engineered target proteins within cells and animals. Here, we design and develop the BromoTag, a new inducible degron sy…
View article: The rise and rise of protein degradation: Opportunities and challenges ahead
The rise and rise of protein degradation: Opportunities and challenges ahead Open
The transformational mechanism of action underpinning targeted protein degradation strategies, including proteolysis-targeting chimeras (PROTACs), gives potential for potent in vivo pharmacology and has allowed projects to move rapidly to …
View article: Sustained Enzymatic Activity and Flow in Crowded Protein Droplets
Sustained Enzymatic Activity and Flow in Crowded Protein Droplets Open
Living cells harvest energy from their environments to drive the chemical processes that enable life. We introduce a minimal system that operates at similar protein concentrations, metabolic densities, and length scales as living cells. Th…
View article: Translating PROTAC chemical series optimization into functional outcomes underlying BRD7 and BRD9 protein degradation
Translating PROTAC chemical series optimization into functional outcomes underlying BRD7 and BRD9 protein degradation Open
Proteolysis targeting chimeras (PROTACs) are complex molecules to design and optimize as degraders, primarily because the linker that bridges the two binding ligands is a highly variable element of design, yet critical for simultaneous eng…
View article: Trivalent PROTACs enhance protein degradation through cooperativity and avidity
Trivalent PROTACs enhance protein degradation through cooperativity and avidity Open
Bivalent small-molecule degraders, or proteolysis targeting chimeras (PROTACs), work by simultaneously binding a target protein and E3 ubiquitin ligase to produce a ternary complex. To drive target ubiquitination and degradation at low cat…
View article: Trivalent PROTACs Enhance Protein Degradation Through Cooperativity and Avidity
Trivalent PROTACs Enhance Protein Degradation Through Cooperativity and Avidity Open
Bivalent small-molecule degraders, or proteolysis targeting chimeras (PROTACs), work by simultaneously binding a target protein and E3 ubiquitin ligase to produce a ternary complex. To drive target ubiquitination and degradation at low cat…
View article: Trivalent PROTACs Enhance Protein Degradation Through Cooperativity and Avidity
Trivalent PROTACs Enhance Protein Degradation Through Cooperativity and Avidity Open
Bivalent small-molecule degraders, or proteolysis targeting chimeras (PROTACs), work by simultaneously binding a target protein and E3 ubiquitin ligase to produce a ternary complex. To drive target ubiquitination and degradation at low cat…
View article: Understanding and Improving the Membrane Permeability of VH032-Based PROTACs
Understanding and Improving the Membrane Permeability of VH032-Based PROTACs Open
Proteolysis targeting chimeras (PROTACs) are catalytic heterobifunctional molecules that can selectively degrade a protein of interest by recruiting a ubiquitin E3 ligase to the target, leading to its ubiquitylation and degradation by the …
View article: Inducible Degradation of Target Proteins through a Tractable Affinity-Directed Protein Missile System
Inducible Degradation of Target Proteins through a Tractable Affinity-Directed Protein Missile System Open
The affinity-directed protein missile (AdPROM) system utilizes specific polypeptide binders of intracellular proteins of interest (POIs) conjugated to an E3 ubiquitin ligase moiety to enable targeted proteolysis of the POI. However, a chem…
View article: Stereoselective Synthesis of Allele-Specific BET Inhibitors
Stereoselective Synthesis of Allele-Specific BET Inhibitors Open
Developing stereoselective synthetic routes that are efficient and cost-effective is important to allow easy access to biologically active molecules. Our previous syntheses of allele-selective bumped inhibitors of the Bromo and Extra-Termi…