Protein Degradation and Inhibitors

Insights From Protein Frustration Analysis Of BRD4-Cereblon Degrader Ternary Complexes Show Separation of Strong from Weak Degraders

This study uses protein frustration analysis to identify key residues distinguishing strong from weak BRD4-Cereblon degraders.

Fluorescence based live cell imaging identifies exon 14 skipped hepatocyte growth factor receptor (MET) degraders

The paper identifies a potent MET degrader using live cell imaging, showing it is more effective than existing PROTACs.

Click Chemistry Enables Rapid Development of Potent sEH PROTACs Using a Direct-to-Biology Approach

This paper develops a miniaturized Direct-to-Biology platform for rapid PROTAC degrader synthesis and screening, identifying potent sEH degraders with subnanomolar activity.

Challenges in predicting PROTAC-mediated Protein-Protein Interfaces with AlphaFold reveal a General Limitation on Small Interfaces

The paper evaluates AlphaFold's ability to predict PROTAC-mediated protein interfaces and finds it struggles with small interfaces, impacting PROTAC design.

Investigating Protein Degradability through Site-Specific Ubiquitin Ligase Recruitment

This paper demonstrates a method to enhance protein degradation by recruiting E3 ligases to specific protein sites, showing improved degradation of target proteins and informing PROTAC development.

Degradation of LMO2 in T cell leukaemia results in collateral breakdown of transcription complex partners and causes LMO2-dependent apoptosis

This study shows that degrading LMO2 in T cell leukemia leads to loss of its DNA-binding partners and apoptosis, suggesting therapeutic potential for LMO2-targeting drugs.

The CECR2 bromodomain displays distinct binding modes to select for acetylated histone proteins versus non-histone ligands.

This paper investigates the binding specificity of CECR2-BRD to acetylated histone and non-histone ligands, revealing distinct binding modes and functional roles in chromatin regulation and inflammation.

Rationalize the Functional Roles of Protein-Protein Interactions in Targeted Protein Degradation by Kinetic Monte-Carlo Simulations

This study uses kinetic Monte-Carlo simulations to model protein-protein interactions in PROTAC-induced ternary complex formation, showing that cooperativity affects association into native-like configurations.

P4ward: an automated modelling platformfor Protac ternary complexes

P4ward is an automated platform for modelling Protac ternary complexes, achieving high hit rates and improved pose ranking compared to existing methods.

Degradation of intrinsically disordered proteins using proteolysis targeting nanobody conjugate

This study introduces PROTNC, a system for degrading intrinsically disordered proteins, and demonstrates its effectiveness in targeting TPX2 to inhibit cancer cell proliferation.

A Kinetic Scout Approach Accelerates Targeted Protein Degrader Development

This study develops a kinetic scout approach to accelerate targeted protein degrader development by tuning ligand residence time through chemical proteomics and mechanistic assays.

Discovery of CRBN-dependent WEE1 Molecular Glue Degraders from a Multicomponent Combinatorial Library

The paper identifies CRBN-dependent WEE1 molecular glue degraders through combinatorial library screening and medicinal chemistry, providing structural insights into kinase selectivity.

Efficient Sampling of PROTAC-Induced Ternary Complexes

The paper introduces a method for efficiently sampling PROTAC-induced ternary complexes, validated on 40 co-crystallized structures with high accuracy and speed.

Monitoring lysosomal catabolism: a sensitive probe for assessing targeted lysosomal degradation of extracellular proteins

The paper develops a fluorescent probe to monitor lysosomal catabolism of internalized proteins and applies it to assess therapeutic LYTAC agents.

In vivo-Active Soluble Epoxide Hydrolase-targeting PROTACs with Improved Potency and Stability

This paper develops next-generation sEH-targeting PROTACs with improved potency and stability, showing effective degradation in mouse tissues.

Discovery of electrophilic degraders that exploit SNAr chemistry

This study develops electrophilic degraders using SNAr chemistry, enabling selective protein degradation without requiring a defined E3 ligase recruiter.

DNA-templated spatially controlled proteolysis targeting chimeras for CyclinD1-CDK4/6 complex protein degradation

This paper introduces DNA-templated PROTACs (DTACs) that enable precise spatial control over protein degradation, showing enhanced selectivity and potency in degrading the CyclinD1-CDK4/6 complex.

Predicting Degradation Potential of Protein Targeting Chimeras

The paper presents a machine-learning pipeline to predict PROTAC degradation potential using compound fingerprints and a graph neural network, achieving better performance than existing methods.

Resistance of estrogen receptor function to BET bromodomain inhibition is mediated by transcriptional coactivator cooperativity

The paper shows that BET bromodomain inhibition does not repress estrogen receptor oncogenic targets due to transcriptional coactivator cooperativity.

PROTAC-induced Protein Structural Dynamics in Targeted Protein Degradation

This study computationally models PROTAC-induced protein dynamics to explain variation in degradation potency despite identical warheads.

Discovery of Potent Degraders of the Dengue Virus Envelope Protein

This study develops small molecule degraders of the dengue virus envelope protein, demonstrating their ability to induce proteosome-mediated degradation and providing a foundation for antiviral drug development.

Paralogue-selective degradation of the lysine acetyltransferase EP300

This study develops a small molecule, MC-1, that selectively degrades EP300 over CREBBP, revealing factors governing paralogue-specific degradation and its impact on cancer cell proliferation.

Lysineless HiBiT and NanoLuc Tagging Systems as Alternative Tools Monitoring Targeted Protein Degradation

This study introduces lysineless HiBiT-RR and nLucK0 tagging systems to reduce degradation artifacts in monitoring protein degradation, showing HiBiT-RR retains sensitivity and nLucK0 shows different degradation patterns than nLucWT.

Identification of Suitable Target/E3 Ligase Pairs for PROTAC Development using a Rapamycin-induced Proximity Assay (RiPA)

This paper introduces a rapamycin-induced proximity assay (RiPA) to identify effective E3 ligase-target pairs for PROTAC development, demonstrating its ability to predict degradation capabilities.

Systematic profiling of the acetyl lysine machinery reveals a role for MAPKAPK2 in bromodomain inhibitor resistance

This study maps the acetyl lysine machinery interactions and identifies MAPKAPK2 as a factor contributing to resistance to BET bromodomain inhibitors in melanoma.

Degron-based bioPROTACs for controlling signaling in CAR T cells

This paper introduces bioPROTACs, a genetic tool to control CAR T cell signaling by degrading specific proteins, demonstrating its effectiveness in inhibiting CAR signaling in human T cells.

P-NADs: PUX-based NAnobody Degraders for Ubiquitin-Independent Degradation of Target Proteins

This paper introduces P-NADs, a ubiquitin-independent protein degradation method using PUX-adaptor proteins and nanobodies, demonstrating their efficacy in human cells and potential for therapeutic applications.

Unveiling the Power of PROTAC Valency: Navigating Cell Type-Specific Hook Effects

The paper evaluates the impact of PROTAC valency on hook effects, showing that trivalent PROTACs do not eliminate the hook effect but may alter its dynamics.

A chemical probe to modulate human GID4 Pro/N-degron interactions

The paper introduces PFI-7, a chemical probe that inhibits GID4 Pro/N-degron interactions, revealing non-degradative roles of the CTLH complex in human cells.

Structural Basis of Conformational Dynamics in the PROTAC-Induced Protein Degradation

The paper analyzes conformational dynamics in PROTAC-induced protein degradation using crystal structures and mathematical modeling, finding that ternary complex rigidity does not enhance degradation and that salt bridges may improve efficiency.