Protein Degradation and Inhibitors

Expanding the Ligandable Chemical Space of OTUB1 through Discovery of a Four-Membered-Ring Recruiter Chemotype

The paper identifies a new four-membered-ring chemotype that selectively binds OTUB1, expands its ligandable chemical space, and enables the development of next-generation DUBTACs.

A Mammalian High-Throughput Screen for AI-Designed Peptide-Guided Protein Degraders

This paper presents a high-throughput platform for screening peptide-guided protein degraders in mammalian cells, demonstrating their ability to reduce target protein abundance and function.

De novo Design of Macrocyclic Molecular Glues

This paper introduces EvoBind-multimer, a deep learning framework for designing molecular glues from protein sequences, demonstrating its ability to recruit E3 ligases to oncoproteins and showing context-dependent functionality.

An iteratively curated CRISPR library reveals target-specific biological resistance landscapes across targeted protein degraders

The paper develops a CRISPR library for TPD-compatible screens to better identify genetic interactions downstream of protein degradation by reducing UPS resistance dominance.

TROP2-targeting chimeras (TRTACs) for tumor-selective membrane protein degradation and enhanced drug delivery

This paper introduces TRTACs, TROP2-targeting chimeras that selectively degrade tumor membrane proteins and deliver drugs, showing efficacy against EGFR and HER2-positive tumors with minimal toxicity.

BET BD2 inhibition facilitates SPOP-mediated degradation of chromatin-associated BRD4/BRD4-NUT, a therapeutic vulnerability in NUT carcinoma

The paper shows that selective inhibition of BRD4-BD2 promotes SPOP-mediated degradation of BRD4/BRD4-NUT in NUT carcinoma, leading to better therapeutic outcomes than pan-BET inhibition.

Reprogramming VHL with molecular glues enables selective degradation of caspase-2

This study develops VHL molecular glues that selectively degrade caspase-2, expanding the substrate range of VHL-based degraders and providing tools to study caspase-2's role in apoptosis and stress.

MG2Act: A Mechanism-Inspired Sequential Attention Framework for Molecular Glue Degradation Prediction

MG2Act predicts molecular glue degradation by modeling sequential interactions between E3 ligase and substrate, outperforming baselines and identifying new degraders.

PhenoDEL as a Novel Screening Strategy Based on Intracellular Protein Degradation Activity

PhenoDEL identifies small molecules that induce protein degradation using a DNA-encoded library screening platform with single-cell resolution.

Mapping the latent CRBN-molecular glue degrader interactome

The paper identifies CRBN-pomalidomide binders using a combination of GluePCA and AI-derived protein surface queries, revealing known and novel interactors for MGD development.

Discovery and Development of First-in-Class Cereblon-Recruiting RIPK1 Degraders

This study develops LD5095, a novel cereblon-recruiting RIPK1 degrader, showing potent RIPK1 degradation and tumor sensitization to immune checkpoint inhibitors.

De novo designed bifunctional proteins for targeted protein degradation

This paper designs de novo bifunctional proteins for targeted protein degradation, demonstrating their ability to degrade BCL-xL in cells.

Bexobrutideg: A Selective, Catalytic Degrader of Bruton's Tyrosine Kinase Overcomes Inhibitor Resistance and Suppresses Autoantibody-Mediated Disease

Bexobrutideg is a BTK degrader that overcomes inhibitor resistance and suppresses autoimmune disease by catalytically degrading BTK.

BRD4 binds the nucleosome via both histone and DNA interactions

This study reveals how BRD4 binds nucleosomes through both histone and DNA interactions, showing that acetylation of H4 influences the BRD4/nucleosome complex conformation.

PROTAC-Mediated Targeting of IKKβ and NR4A1 for AML Therapy

This paper identifies IKKβ and NR4A1 as drivers of AML and develops a PROTAC to degrade them, showing potent cytotoxicity and reduced leukemia progression in mice.

HNF1A is a novel BRD4 target and critical for BET-inhibitor response in pancreatic ductal adenocarcinoma

This paper identifies HNF1A as a BRD4 target and shows that BET-inhibitors' antitumor effects in PDAC depend on HNF1A ablation.

Systematic Targeting of Protein Complexes with Molecular COUPLrs

The paper introduces molecular COUPLrs to systematically target protein complexes, identifying new glue classes and their interactions in cancer cell lines.

An Optimized RNF126-Targeting Covalent Handle for Molecular Glue Degraders

This paper develops an optimized covalent handle targeting RNF126 to create molecular glue degraders, showing improved selectivity and reduced cytotoxicity compared to a fumarate-based handle.

Assessing the Stability of Molecular Glues with Weighted Ensemble Simulations

This study uses weighted ensemble simulations to assess how molecular glues stabilize protein-protein interactions, showing distinct behaviors that correlate with reported EC50 values.

A Bivalent Molecular Glue Linking Lysine Acetyltransferases to Oncogene-induced Cell Death

This paper develops KAT-TCIPs to induce cell death in diffuse large B cell lymphoma by redirecting p300 and CBP to activate programmed cell death genes repressed by BCL6.

Combinatorial screening of biological degrader modules identifies heterobifunctional molecules that efficiently destroy MYC, leading to rapid tumour cell death in vitro and in vivo

A novel AR molecular glue degrader via bivalent engagement of the N-terminal domain and RNF213-UBE2J2 complex

This paper introduces GZL626, a novel AR degrader that targets the N-terminal domain and RNF213-UBE2J2 complex, effectively degrading AR and AR-V7 and showing antitumor and antiviral activity.

Covalent remodeling of CRBN creates a non-canonical neosubstrate interface with NTAQ1

The paper shows that covalent modification of CRBN by EM12-FS creates a new interface for NTAQ1 recruitment, expanding degrader specificity beyond the G-loop degron.

Therapeutic targeting of MYC- and MYCN-driven medulloblastoma with a novel MYC degrader molecule

This study identifies UNSW-SC-22 as a novel MYC/MYCN-targeting molecule that crosses the blood-brain barrier and shows potent preclinical efficacy in medulloblastoma.

SynPROTAC: synthesizable PROTACs design through synthesis constrained generative model and reinforcement learning

SynPROTAC generates novel PROTAC molecules with feasible synthetic routes and favorable properties using a synthesis-constrained generative model and reinforcement learning.

RAF1 scaffold integrity shapes chemogenetic degradation outcomes in KRAS-driven lung cancer

This study shows that chemogenetic degradation of RAF1 in KRAS-driven lung cancer does not replicate genetic ablation outcomes due to scaffold disruption.

The extra-terminal domain drives the role of BET proteins in transcription

This study identifies the extra-terminal domain as essential for BET protein function in transcription and chromatin occupancy.

Native Mass Spectrometry Analysis of Cullin RING Ubiquitin E3 Ligase Complexes in the Context of Targeted Protein Degradation

This study uses native mass spectrometry to characterize CRL2VHL complexes and their interactions with PROTACs and POIs, revealing key multiprotein assemblies involved in targeted protein degradation.

Tumor-selective Mcl1 degradation by AUTAC uncouples antitumor efficacy from cardiotoxicity

This paper shows that AUTAC selectively degrades Mcl1 in tumors without affecting the heart, improving antitumor efficacy while avoiding cardiotoxicity.

Discovery of CDK4-selective molecular glue degraders by high-throughput proteomics

This study identifies a CDK4-selective molecular glue degrader, NE26394, using high-throughput proteomics, showing its efficacy in CDK4-dependent cancer models.