Protein Degradation and Inhibitors

Design of Tissue-Selective PROTACs Through Recruiting E3 Ligase Scaffolding Protein MAGEA11

This paper designs a PROTAC that recruits the tissue-specific E3 ligase MAGEA11 to degrade BET proteins in cancer cells, showing selectivity in osteosarcoma and esophageal squamous cell carcinoma lines.

Uptake of CD36 and its natural and therapeutic ligands by clathrin-mediated endocytosis

This study shows CD36 and its ligands are internalized via clathrin-mediated endocytosis, not caveolae, and disrupting clathrin inhibits ligand uptake and PROTAC-induced degradation.

HaloPROTAC-mediated degradation reveals SOX10-dependent gene expression changes in melanoma cells

This study uses HaloPROTAC-mediated SOX10 degradation in melanoma cells to identify novel SOX10 target genes and reveal its role in drug resistance and metastasis.

ELiAH2: update of the atlas of E3 ligases in human tissues by integrating tissue-specificity and docking properties of ligands for targeted protein degradation

ELiAH2 expands the E3 ligase atlas by integrating tissue-specific RNA-seq and docking data to support targeted protein degradation candidate prioritization.

Allosteric covalent inhibition of cereblon through cryptic cysteine targeting

The paper identifies covalent ligands targeting a cryptic cysteine in CRBN, demonstrating their ability to inhibit neosubstrate degradation by trapping CRBN in an inactive conformation.

E3 Ligase Ligandalyzer: A Structure-First, Ligand-Centric Platform for E3 Ligase Recruiter Selection

E3 Ligase Ligandalyzer provides a platform for exploring E3 ligase-recruiter complexes, enabling analysis of chemical and structural data to support degrader design.

Cereblon on Steroids: Beyond the Canonical Ligand Space

This paper expands the known ligand space of Cereblon by identifying new chemically distinct ligands that bind through non-canonical mechanisms.

A ncBAF to cBAF Switch Regulates Human Hematopoietic Progenitor Myeloid Differentiation

This study shows that BRD9 regulates myeloid differentiation in human HSPC by switching ncBAF to cBAF, leading to increased MDSC generation and IL-8 secretion.

Chameleonicity Beyond Compactness: Conformational Persistence and Passive Permeability Across 20 PROTAC Ensembles

This study investigates the conformational properties of 20 PROTACs to determine factors influencing their passive permeability, finding that compactness alone is not sufficient and introducing a new metric, maximum ring size.

Single-Atom Modification Enables Reversal of Degradation Selectivity between NSD2 and GSPT1

This study modifies a molecule to create two variants with different target selectivity, showing how small structural changes can control degradation activity.

Native Mass Spectrometry Reveals Distinct Effects of Linker Length and Targeting-Ligand Identity on PROTAC Ternary Complexes

This study uses native mass spectrometry to show how PROTAC linker length and targeting ligand affect ternary complex structure and stability.

SMYD3 protein degraders in HPV-negative head and neck squamous cell carcinoma.

This study develops SMYD3 proteolysis targeting chimeras (PROTACs) for HPV-negative head and neck squamous cell carcinoma, showing effective SMYD3 degradation and reduced oncogenic activity.

Performance of Rilpivirine-Based Hydrophobic Tags and PROTACs Directed Against HIV-1 Reverse Transcriptase

The paper evaluates rilpivirine-based hydrophobic tags and PROTACs for HIV-1 RT degradation, finding that PEG4-Ad shows low nanomolar potency but limited efficacy against resistance mutations.

PROXINAUT: An Automation Platform for Rapid Hit-to-Degrader Discovery

PROXINAUT automates hit-to-degrader discovery by integrating library screening with parallel synthesis, resulting in validated degraders with improved binding affinity.

DesignMaster: A Multi-Conditional Diffusion Framework for Rational PROTAC Design

DesignMaster improves PROTAC design by incorporating linker length and physicochemical constraints through a diffusion framework, achieving better validity and recovery than existing methods.

Single Amino Acid Disease Mutations Act as Genetic Glues to Drive Neo-substrate Degradation

The paper identifies single amino acid mutations that create functional degrons in transcription factors, enabling targeted protein degradation and revealing a new mechanism for disease-related protein turnover.

MAPK signaling links BRD2 chromatin occupancy to PI3K/AKT inhibitor sensitivity

This study identifies BRD2 as a co-targetable vulnerability with PI3K/AKT inhibitors in breast cancer, showing that BRD2 phosphorylation is required for chromatin binding and that targeting BRD2 enhances drug efficacy.

Beyond Dmax and DC50: A simple tool to evaluate the complex PROTAC-mediated kinetic degradation dynamics

The paper introduces a simple live-cell imaging assay to rapidly measure multiple PROTAC degradation metrics for comparing and ranking PROTACs.

Ubiquitin Receptor-Induced Proximity is Sufficient for Ubiquitin-Independent Targeted Protein Degradation via the 26S Proteasome

This paper introduces Protea-Tac, a Ub-independent protein degrader that targets proteins to the proteasome, demonstrating in vivo tumor suppression.

dubTAGs enable on-demand stabilization for tunable and reversible control of endogenous protein levels

The paper introduces dubTAGs, small molecules that stabilize proteins tagged with FKBP12F36V by recruiting deubiquitinases, enabling tunable and reversible control of protein levels.

Data-independent acquisition (DIA) approach for comprehensive ubiquitinome profiling in targeted protein degradation

This study develops a DIA-based workflow for comprehensive ubiquitinome profiling in targeted protein degradation, identifying over 40,000 ubiquitylated peptides.

A Proximity-Driven Functional Screening Platform for the Discovery of Noninhibitory USP7 Ligand Enabling Targeted Protein Stabilization

This paper introduces a proximity-driven screening platform to identify noninhibitory DUB ligands, discovering a USP7 ligand that enables targeted protein stabilization.

Leveraging High-Throughput Proteomics and AI-Based Protein Folding to Accelerate VAV1 Molecular Glue Discovery

This paper identifies a novel non-canonical RT-loop degron in VAV1 and demonstrates how conformational restriction and computational modeling enhance molecular glue potency for proteasomal degradation.

Identification and SAR optimization of FBXO22-mediated TEAD Targeted Glue degraders

This study identifies and optimizes TEAD-targeted glue degraders using an aldehyde-mediated degron mechanism, achieving improved degradation potency and kinetics.

Protein Age Bias in Target Degradation by PROTACs

This study identifies protein age as a factor affecting PROTAC efficacy, showing that pre-existing proteins are degraded more efficiently than newly synthesized ones.

Enzyme Activation of Triggerable Polymeric Lysosome Targeting Chimeras

This paper introduces tPolyTACs, a covalent enzyme-responsive platform for extracellular protein degradation, showing enhanced selectivity and efficiency by using phosphatase-cleavable substrates to trigger lysosomal targeting.

Pro-GAT: Reconnecting Fragmented PROTACs Using Graph Attention Transformer

Pro-GAT repairs chemically disconnected PROTAC candidates generated by diffusion models, improving validity while maintaining uniqueness.

FlexiTAC enables controllable PROTAC linker generation across diverse structural settings using a Bayesian flow network with posterior guidance

FlexiTAC generates controllable PROTAC linkers using a Bayesian flow network, improving validity and pose quality over existing methods.

Programmable protein degraders enable selective knockdown of pathogenic β-catenin subpopulations in vitro and in vivo

This paper develops programmable protein degraders (uAbs) that selectively knock down pathogenic β-catenin in vitro and in vivo, reducing tumor cell survival and proliferation.

DIPTAR: A synthetic biology platform for functional interrogation of protein degradation

DIPTAR converts protein degradation into a selectable phenotype to enable functional studies of degradation pathways and host-pathogen interactions.