Protein Degradation and Inhibitors

Design and Validation of the First-in-Class PROTACs for Targeted Degradation of the Immune Checkpoint LAG-3

This study designs and validates the first-in-class PROTACs for LAG-3 degradation, showing dose-dependent reduction in LAG-3 protein levels in Raji-LAG3 cells.

PSP-0119: Targeted IRAK4 Degradation as a Novel Therapeutic Strategy for FLT3-Mutant AML

This study identifies PSP-0119, an IRAK4 degrader, as a promising therapy for FLT3-mutant AML by inhibiting IRAK4 activity and showing antileukemic effects in cell lines and xenograft models.

Interpretable PROTAC degradation prediction with structure-informed deep ternary attention framework

This paper introduces PROTAC-STAN, a deep learning framework for interpretable PROTAC degradation prediction, achieving improved accuracy and model interpretability.

Frustration in the Protein-Protein interface Plays a Central Role in the Cooperativity of PROTAC Ternary Complexes

This study shows that frustration in the SMARCA2-VHL protein-protein interface correlates with PROTAC cooperativity, offering a framework for structure-based PROTAC design.

Computational design of pH-sensitive binders

This paper introduces computational methods to design pH-sensitive binders that dissociate under acidic conditions, demonstrating their application in targeting various receptors and proteins.

Sulfinyl Aziridines as Stereoselective Covalent Destabilizing Degraders of the Oncogenic Transcription Factor MYC

This paper identifies a sulfinyl aziridine compound that selectively degrades MYC by targeting specific residues in its intrinsically disordered regions, demonstrating the potential of chiral small molecules for targeting undruggable proteins.

Peptide molecular glues select between BET paralogues by exploiting allosteric sites and conformational dynamics

The paper identifies cyclic peptides that selectively inhibit BET BD paralogues by exploiting sequence differences and conformational dynamics, achieving high selectivity over existing inhibitors.

Network-driven identification of indisulam neo-substrates for targeted protein degradation

The paper identifies new neo-substrates of the molecular glue indisulam using network analysis and proteomics, validating one candidate through experimental testing.

Acetylation-dependent clustering of BRD2 instructs transcription dynamics

This study shows BRD2 clustering on acetylated chromatin is critical for RNA Polymerase II recruitment and transcription initiation.

Deciphering acquired resistance mechanisms to sustained auxin-inducible protein degradation in cells and mice

This study identifies four resistance mechanisms to sustained auxin-inducible protein degradation in human cells and mice using the AID2 system.

BRD2 bridges TFIID and histone acetylation to promote transcriptional initiation

This study shows BRD2 promotes transcriptional initiation via bromodomain-dependent binding to acetylated histones and recruits TFIID, while BRD4 mediates elongation through CDK9 recruitment.

Gαq-stimulated gene expression is insensitive to Bromo extra terminal domain inhibitors in HEK 293 cells

The paper tests BET protein responsiveness to G protein isoforms in HEK 293 cells and finds Gq-induced gene expression is insensitive to BET inhibitors, while Gs-induced expression is sensitive to BET degradation.

Macropinocytosis-Mediated Recyclable LYTACs (McR-TACs) for Membrane and Extracellular Protein Degradation

This paper develops McR-TACs, a recyclable LYTAC system that degrades cell membrane and extracellular proteins via macropinocytosis, independent of lysosome-shuttling receptors.

A modular toolbox for in cellulo screening of small molecule inhibitors targeting chromatin reader domains

The paper develops a modular cell line platform with synthetic chromatin reader constructs to assess small molecule inhibitors targeting bromodomains in living cells.

Temporal and Spatial Characterization of CUL3KLHL20-driven Targeted Degradation of BET family, BRD Proteins by the Macrocycle-based Degrader BTR2004

This study characterizes the temporal and spatial dynamics of BTR2004-mediated degradation of BET family proteins using KLHL20, providing insights for future PROTAC design.

Transcriptional Rewiring of BET Inhibitor Treated Ewing Sarcoma Cells Augments their Dependency on Focal Adhesion Kinase

This study shows that BET inhibitor treatment rewires Ewing sarcoma transcription, increasing dependency on FAK, and that combining BET and FAK inhibitors synergistically reduces tumor growth.

Targeting Pregnane X Receptor with a Potent Agonist-Based PROTAC to Delay Colon Cancer Relapse

This study designs and tests a PXR agonist-based PROTAC (JMV7048) that degrades PXR in cancer cells, reducing chemoresistance and delaying colon cancer relapse.

In-cell proximity target validation methods for heterobifunctional molecules with CRBN- or VHL-binder using AirID

The paper validates target proteins of heterobifunctional molecules using AirID, showing different interactome profiles based on E3 ligase binders.

Characterization of PROTAC specificity and endogenous protein interactomes using ProtacID

This paper introduces ProtacID, a BioID-based method to identify PROTAC-proximal proteins, validates degradation targets, and identifies non-productive interactions in human cells.

SynGlue: AI-Driven Designer for Clinically Actionable Multi-Target Therapeutics

SynGlue is an AI framework that designs multi-target therapeutics by combining data-driven and structure-guided methods, producing potent degraders for BRD4 and GSPT1.

Targeted degradation of the HPV oncoprotein E6 reduces tumor burden in cervical cancer

This study develops a PROTAC that degrades HPV E6 protein, reducing tumor burden in a mouse model and showing immune dependence.

LYMTACs: Chimeric Small Molecules Repurpose Lysosomal Membrane Proteins for Target Protein Relocalization and Degradation

This paper introduces LYMTACs, small molecules that use lysosomal membrane proteins to target and degrade membrane proteins, showing effectiveness against KRASG12D.

Single-Assay Characterization of Ternary Complex Assembly and Activity in Targeted Protein Degradation

This paper introduces a fluorescent assay to quantify ubiquitination kinetics in targeted protein degradation, enabling measurement of degrader and ligase affinities and ternary complex activity.

Unbiased mapping of cereblon neosubstrate landscape by high-throughput proteomics

Proteomics and ubiquitinomics screening of 100 CRBN ligands in two cell lines validated 50 novel neosubstrates and yielded selective phenyl glutarimide degraders of KDM4B, G3BP2 and VCL.

Development of Degraders and 2-pyridinecarboxyaldehyde (2-PCA) as a recruitment Ligand for FBXO22

This paper develops chemical probes for FBXO22, including a degrader and a recruitment ligand, to enable targeted protein degradation applications.

Targeted degradation of GSPT1 and NEK7 by a molecular glue prodrug for treatment of HCC

The paper identifies ABS-752, a molecular glue prodrug that degrades GSPT1 and NEK7 in HCC cells, showing potent in vitro and in vivo activity.

p53Y220C-BET-bifunctionals (tPRIMEs) drive p53Y220C-mutant cancer cells into apoptosis

This study develops p53Y220C-tPRIMEs, bifunctional molecules that induce ternary complexes with p53Y220C and BET proteins, leading to apoptosis and growth inhibition in p53 mutant cancer cells.

A Lipid Prodrug Strategy Enhances Targeted Protein Degrader CNS Pharmacokinetics

This study identifies fatty acid promoieties that improve CNS exposure of targeted protein degraders by enhancing pharmacokinetics and BBB permeability.

Dual E3 ligase recruitment by monovalent degraders enables redundant and tuneable degradation of SMARCA2/4

This study shows that a monovalent MGD can recruit two E3 ligases redundantly to degrade SMARCA2/4, with tunable ligase preference through chemical and genetic modifications.

Covalent Modulators of Immune Regulatory Transcription Factors IRF8 and IRF5

This paper identifies covalent modulators that target and degrade IRF5 and IRF8, key inflammatory transcription factors, with TH-B10 showing potent and selective degradation of IRF8.