Protein Degradation and Inhibitors

Monovalent Pseudo-Natural Product Degraders Supercharge the Native Degradation of IDO1 by KLHDC3

The paper identifies iDegs, which enhance IDO1 degradation via the native CRL2KLHDC3 pathway, reducing kynurenine formation and offering new therapeutic potential for cancer.

Polymeric Lysosomal-Targeting Chimeras: Extracellular Targeted Protein Degradation Without Co-opting Lysosome-Targeting Receptors

This paper introduces PolyTACs, a polymer-antibody conjugate platform for extracellular protein degradation without lysosome-targeting receptors, demonstrating efficacy against three membrane proteins and soluble targets.

Systematic characterization of cancer-associated SPOP mutants reveals novel and reprogrammable degradative activities

This study characterizes cancer-associated SPOP mutants, showing their degradative activities and potential for therapeutic repurposing.

Development of PROTACs for targeted degradation of oncogenic TRK fusions

This paper develops PROTACs to degrade oncogenic TRK fusions, showing improved efficacy compared to traditional inhibitors.

ProxiCapture Reveals Context-Dependent CRBN Interactome Landscape of Molecular Glue Degraders

ProxiCapture identifies context-dependent CRBN interactors of molecular glues across diverse cell types and tissues, revealing a comprehensive atlas of pomalidomide targets.

Tipping the balance: Synthesis and evaluation of centrinone-based degraders of polo-like kinase 4

The paper develops and evaluates centrinone-based degraders of PLK4, finding that some lower PLK4 levels via degradation while others increase them by inhibiting autoregulation.

PCMT1 generates the C-terminal cyclic imide degron on CRBN substrates

The paper identifies PCMT1 as an enzyme that forms C-terminal cyclic imides on CRBN substrates, linking it to metabolic enzyme regulation and epileptic phenotypes.

Tuning the open-close equilibrium of Cereblon with small molecules influences protein degradation

This study identifies CRBN binders that induce or fail to induce CRBN closure, showing that closure is critical for degrader activity.

Discovery of Non-Degradative Covalent Molecular Glues for Transcriptional Reprogramming

This study identifies ZD-1-186, a non-degradative molecular glue that rewires BCL6 proximity to suppress MYC and induce tumor-suppressive genes in lymphoma cells.

Stereoselective Degradation of Diacylglycerol Kinases Potentiate T cell Activation and Tumor Cell Cytotoxicity

This study identifies a stereoselective DGK inhibitor that enhances T cell activation and tumor cell cytotoxicity through proteasome-dependent degradation of DGK.

Conformational dynamics in the membrane interactions of bispecific targeted degrader therapeutics

This study analyzes over 3500 PROTACs to determine how linker design and molecular properties affect cell permeability and intracellular exposure.

Overcoming Ligand Discovery Challenges: Developing Peptide-Based Tracers for SPSB2

This study develops peptide-based tracers for SPSB2 E3 ligase by conjugating cell-penetrating peptides to degrons, enabling efficient cellular delivery and target engagement assessment.

Ion channel inhibition by targeted recruitment of NEDD4-2 with divalent nanobodies

This study demonstrates the use of divalent nanobodies to recruit NEDD4-2 E3 ligase to degrade ion channels, reducing their function with minimal off-target effects.

Evaluation of Thiol-Mediated Uptake in VHL-Based PROTACs

This study evaluates the cytotoxic effects of VHL-based PROTACs modified with 1,2-dithiolane handles, finding increased or equivalent cytotoxicity in cancer cells compared to unmodified compounds.

Covalent Reprogramming of Kinase Binders to Modulate Protein Homeostasis

The paper shows that adding electrophilic groups to kinase ligands can stabilize or degrade proteins, demonstrating a new way to modulate protein homeostasis through covalent interactions.

Induced ubiquitination bypasses canonical ERAD to drive ER protein degradation

This paper demonstrates that ER membrane proteins can be degraded via cytosolic E3 ligase recruitment, bypassing ERAD and relying on VCP-mediated ubiquitin chain cleavage.

The BRD4-nucleosome interaction is enhanced modestly and non-selectively by histone acetylation

This study investigates BRD4's nucleosomal binding affinity and shows that histone acetylation modestly enhances this interaction, with little dependence on acetylation pattern.

Inhibitor-induced supercharging of kinase turnover via endogenous proteolytic circuits

The paper identifies inhibitor-induced kinase destabilization as a common phenomenon and reveals that it occurs through endogenous proteolytic mechanisms rather than classical ubiquitination.

SINE compounds activate exportin-1 degradation via an allosteric mechanism

This paper reveals that SINE compounds induce XPO1 degradation via an allosteric mechanism involving ASB8, distinct from molecular glue degraders.

Linker-rigidified VHL homodimerizers convert degraders into stabilizers of non-ubiquitinable ternary complexes

Induced ubiquitination of the partially disordered Estrogen Receptor alpha protein via a 14-3-3-directed molecular glue-based PROTAC design

This paper develops a molecular glue-based PROTAC (MGPROTACs) to ubiquitinate the 14-3-3/Estrogen Receptor complex, demonstrating cooperative complex formation and selective ubiquitination through linker design.

A biological PROTAC for α-synuclein.

This paper describes a bioPROTAC targeting α-synuclein that reduces its abundance and aggregates in cell-type dependent manner, but fails for other targets like SOD1 and LMO2.

ELITE: E3 Ligase Inference for Tissue specific Elimination: A LLM Based E3 Ligase Prediction System for Precise Targeted Protein Degradation

The paper introduces a system for predicting tissue-specific E3 ligases for targeted protein degradation using a BERT-based model and integrated biological data.

In vitro Characterization of Peptidomimetic Proteolysis Targeting Chimera (PROTAC) as a Degrader of 3-Chymotrypsin-Like Protease (Mpro/3CLpro) against SARS-CoV-2

The paper characterizes FT235, a PROTAC degrader of SARS-CoV-2 3CLpro, showing antiviral activity and reduced cytotoxicity.

Selective degradation of BRD9 by a DCAF16-recruiting targeted glue: mode of action elucidation and in vivo proof of concept

The paper identifies a potent BRD9 degrader, AMPTX-1, which selectively recruits BRD9 to DCAF16, leading to its degradation in vivo.

Design, Optimization and Development of RIPK1 Degraders with Improved Pharmacokinetic and Pharmacodynamic Properties

This study designs and evaluates a novel RIPK1 degrader, LD5097, showing potent degradation activity, favorable pharmacokinetics, and enhanced antitumor effects in cancer models.

Proteome-Wide Discovery of Degradable Proteins Using Bifunctional Molecules

The paper introduces AgnoTACs, bifunctional molecules that enable proteome-wide discovery of degradable proteins, identifying over 50 previously untargeted proteins.

The cysteine-reactive covalent RNF4 ligand CCW16 induces ferroptosis in AML cells by activation of ROS signaling

This study shows that the RNF4 ligand CCW16 induces ferroptosis in AML cells through a RNF4-independent mechanism by causing covalent protein modifications and upregulating ferroptosis markers.

Hydralazine inhibits cysteamine dioxygenase to treat preeclampsia and senesce glioblastoma

This paper identifies hydralazine as an inhibitor of cysteamine dioxygenase (ADO), showing its role in treating preeclampsia and inducing senescence in glioblastoma.

Multiplex design and discovery of proximity handles for programmable proteome editing

The paper develops a method to discover new effector handles for proteome editing by combining de novo protein design with multiplex screening, identifying handles for degradation and stabilization of target proteins.