Protein Degradation and Inhibitors

Phosphorylation-driven Targeted Protein Degradation of Oncogenic β-catenin

This study identifies induced-proximity drugs that target β-catenin in colorectal cancer by recruiting Casein kinase I, leading to its degradation and inhibiting tumor growth.

Inducing TRIB2 Targeted Protein Degradation to Reverse Chemoresistance in Acute Myeloid Leukemia

This study identifies TRIB2 as a therapeutic target in AML by demonstrating that its degradation via PROTACs and small molecules can reverse chemoresistance and enhance chemotherapy efficacy.

Molecular Glue-Induced Homodimerization Drives Targeted CRBN Autodegradation

This paper introduces LJY-3-60, a molecular glue that induces CRBN homodimerization and autodegradation, providing a tool for controlled protein degradation.

Integrated proteomic screening reveals design principles of CRBN molecular glue degraders

The paper identifies new CRBN neosubstrates using proteomic screening and machine learning, expanding the landscape of molecular glue degraders.

Design, synthesis, and pharmacological evaluation of novel PROTAC degraders targeting 11β-HSD1 for metabolic disease intervention

This study develops and evaluates PROTAC degraders targeting 11β-HSD1, showing improved glucose tolerance and insulin secretion in a T2DM mouse model.

NanoBRET Tracer Development for Class I Bromodomain Target Engagement in Live Cells

The paper develops a NanoBRET tracer, MS-1, to assess functional activity of class I bromodomain inhibitors in live cells, showing broad applicability across BPTF, PCAF, GCN5, and CECR2.

GlueFinder: A Data-Driven Framework for the Rational Discovery of Molecular Glues

GlueFinder identifies molecular glue binding sites near protein interfaces, enabling rational design of degraders that recruit diverse E3 ligases to therapeutic targets.

Direct-to-Biology Enables Rapid Identification of Potent FBXO22 Degraders

The paper tests PROTACs targeting FBXO22 and finds no degradation of four targets but identifies potent FBXO22 homo-PROTACs and CRBN/VHL-mediated degraders.

Determination of the cellular target engagement by direct-to-biology Cellular Thermal Shift Assay (CETSA)

This paper demonstrates a direct-to-biology CETSA approach to evaluate cellular target engagement without purification, showing unpurified compounds can be used for assessment.

Reprogramming CAR T-Cells with designed bioPROTACs

This paper demonstrates that bioPROTACs can reprogram CAR T-cells by targeting DNMT3A, offering a tunable alternative to gene editing for enhancing T-cell function.

A Scalable Design for Proximity-Inducing Molecules

This paper introduces GRIPs, a scalable platform for PTM editing using chimeric molecules, demonstrating functionality in multiple systems and confirming specificity through proteomics.

Targeted shedding of extracellular membrane proteins by induced protease recruitment

This paper develops Shedders, bispecific antibodies that recruit ADAM10 to induce ectodomain shedding of cell surface proteins, demonstrating efficacy in depleting LAG-3 and identifying new targets for therapeutic intervention.

High-throughput diversification of protein-ligand surfaces to discover chemical inducers of proximity

This study uses high-throughput chemistry to discover chemical inducers of proximity by modifying pre-existing ligands and screening for degrader activity.

On-target toxicity of GSPT1 molecular glue degraders in mice

The paper investigates the on-target toxicity of GSPT1 molecular glue degraders in mice, showing that GSPT1 depletion causes severe systemic toxicity, which is rescued by a degradation-resistant mutant.

Sub-stoichiometric Degradation is Dispensable for Potent PROTACs: A Case Study for Irreversible Covalent BTK Degraders

This paper develops and characterizes PSIRC3, a covalent PROTAC for BTK, showing it achieves potent degradation with sub-nanomolar potency and high selectivity, challenging the necessity of catalytic turnover for PROTAC efficacy.

Sheddase Targeting Chimeras (SHEDTACs) catalyze membrane target proteolysis

This paper introduces SHEDTACs, bispecific antibodies that use cell surface proteolysis to degrade membrane targets, showing effectiveness in depleting LAG3 and PD-1 on T cells.

Reconciling Cooperativity Definition in PROTACs and Molecular Glues: Thermodynamic Dissection into PPI and Ligand Entropic Contributions

The paper analyzes thermodynamic contributions to cooperativity in PROTACs and molecular glues, revealing entropic penalties from ligand exposure and reconciling conflicting definitions.

Molecular basis of BET family protein inhibition by four clinical-stage small-molecule inhibitor drugs

This study investigates how four BET inhibitors bind to BRD2's bromodomain, revealing a shared mechanism of competitive inhibition and highlighting structural differences that may affect their pharmacological properties.

A pharmacological modality to sequester homomeric proteins

This paper introduces PINCHs, bifunctional molecules that sequester homomeric proteins by inducing polymerization, demonstrating efficacy in knocking down protein function in cells.

A compact, portable degron tool derived from the 3'UTR of MTCH2 for tunable degradation of proteins

The paper describes a nine-amino-acid degron derived from MTCH2's 3'UTR that enables tunable protein degradation via the ubiquitin-proteasome system.

Structure-guided design of a targeted autoantibody degrader for neurologic disease

This paper designs a targeted autoantibody degrader to treat neurologic diseases by specifically clearing pathogenic autoantibodies while preserving the immune system.

Developing Potent and Selective TBK1 Molecular Glue Degraders for Cancer Immunotherapy

This paper develops a first-in-class TBK1 molecular glue degrader, CCT412020, which enhances anti-tumour immunity and overcomes immune checkpoint blockade resistance.

Modulation of the 14-3-3σ/C-RAF autoinhibited complexby molecular glues

This paper designs molecular glues that stabilize the 14-3-3/C-RAF autoinhibited complex, showing selectivity and functional effects in biophysical and cell assays.

Identification of clofibric acid as a SYVN1 ligand for PROTAC development

This paper identifies clofibric acid as a SYVN1 ligand and demonstrates its use in developing SYVN1-dependent BRD4 PROTACs with improved degradation efficiency.

Discovery and characterization of small molecule inhibitors of CBL-B that act as intramolecular glue to enhance T-cell anti-tumor activity

Click. Screen. Degrade. A Miniaturized D2B Workflow for rapid PROTAC Discovery

This paper introduces a miniaturized PROTAC synthesis workflow that bypasses compound purification, enabling rapid screening and degradation assessment of multiple targets.

A cytokine receptor-targeting chimera (kineTAC) toolbox for expanding extracellular targeted protein degradation.

The paper expands the kineTAC toolbox by creating 81 new cytokine receptor-targeting chimeras for cell-type-specific extracellular protein degradation.

Coiled-coil scaffolds for Targeted Protein Degradation

The paper demonstrates the use of coiled-coil scaffolds to enable targeted protein degradation by integrating target-binding and degradation motifs into single-polypeptide constructs.

PROTAC-Driven Protective Therapy increases the therapeutic window of anticancer drugs

This paper introduces PROTAC-Driven Protective Therapy (PDPT) to reduce toxicity of anticancer drugs by degrading proteins involved in drug-induced toxicity, showing protection of healthy cells and efficacy in TP53-mutant cancers.

Targeted recruitment of USP15 enhances CTLA4 surface levels and restricts its degradation.

This paper demonstrates that targeted recruitment of USP15 stabilizes CTLA4 at the cell surface by redirecting it from lysosomal degradation, providing a foundation for ENTAC design.