Protein Degradation and Inhibitors

BacPROTACs outperform inhibitors in Mycobacterium tuberculosis

This study develops BacPROTACs, a new class of antibacterial agents targeting M. tuberculosis, showing improved activity over traditional inhibitors.

The NanoBridge system for targeted post-translational modification of challenging proteins

The NanoBridge system enables targeted post-translational modification of challenging proteins in live cells by using biologic binders to direct PTM enzymes to specific targets.

Leveraging AI and structural proteomics for rational design of a KAT6A degrader

The paper develops an AI-driven platform for rational PROTAC design, enabling the optimization of a KAT6A degrader with potent in vivo activity.

Targeted KRAS(G12V) degradation elicits efficient and durable lung adenocarcinoma regression in vivo

This study shows that targeted KRAS(G12V) degradation causes durable lung adenocarcinoma regression in mice, with tumor relapse linked to proteolysis machinery dysregulation.

A bulk cell heterozygous knock-in strategy for targeted protein degradation

This paper introduces a bulk cell heterozygous knock-in strategy for targeted protein degradation, bypassing single-cell cloning and improving expression control.

Targeted protein degradation via CAR endocytosis of antigen in T cells

This paper develops a TPD platform using CAR T cells to degrade extracellular TNF, achieving disease remission in a rheumatoid arthritis model.

Targeted degradation of USP7 in solid cancer cells reveals disparate effects of deubiquitinase inhibition vs. acute protein depletion

This paper compares the effects of USP7 inhibition and degradation in cancer cells, finding distinct phenotypic and proteomic responses.

Proteasome Inhibition Enhances Lysosome-mediated Targeted Protein Degradation

This paper shows that combining proteasome inhibitors with lysosome-targeted degradation enhances cancer cell death by exploiting an adaptive autophagy response.

Z-TAC enables custom and combinatorial degradation of cell surface proteins

Z-TAC converts IgG antibodies into cell-surface protein degraders, enabling efficient and sustained degradation of multiple receptors and receptor combinations.

Exploration of targeted electrophilic kinase probes identifies a covalent ULK1 degrader

The paper identifies covalent ULK1 degraders by modifying ATP-site binding scaffolds to control ULK1 activity and abundance.

Chemoproteomic Characterization of GPX4 Covalent Ligands and Targeted Degradation

The paper characterizes a covalent GPX4 inhibitor and develops degraders, expanding tools for GPX4 targeting.

BRD2 Upregulation as a Pan-Cancer Adaptive Resistance Mechanism to BET Inhibition

This study identifies BRD2 upregulation as a common adaptive resistance mechanism to BET inhibitors across cancers and shows that targeting BRD2 or NFYA can enhance BET inhibitor efficacy.

Proof-of-concept of targeted degradation of p38α/β MAPK host-kinase as a potent inhibitor of coronaviruses.

This paper demonstrates that targeted degradation of p38α/β MAPK using PROTAC NR-7h potently inhibits coronavirus infection with high potency and low cytotoxicity.

Tandem bromodomains of BRD4 cooperatively read poly-acetylated nucleosomes to enhance chromatin engagement and regulate breast cancer phenotypes

This study shows that BRD4's tandem bromodomains cooperatively bind poly-acetylated nucleosomes, enhancing chromatin engagement and influencing breast cancer phenotypes.

Disrupting linearity of PROTAC scaffolds prevents off-target complex I inhibition

The paper identifies that linear PROTAC scaffolds inhibit mitochondrial complex I, leading to ATP depletion, and proposes structural modifications to mitigate this off-target effect.

Structural basis of NSD2 degradation via targeted recruitment of SCF-FBXO22

This paper reveals the structural basis of NSD2 degradation via SCF-FBXO22 recruitment, showing how aldehyde-based degraders induce conformational changes for covalent binding and efficient protein degradation.

Discovery of molecular glues that bind FKBP12 and novel targets using DNA-barcoded libraries

This study identifies novel FKBP12 molecular glues and their targets using DNA-encoded libraries, showing FKBP12-dependent recruitment to BRD9 and QDPR.

Efficient exploration of peptide libraries using active learning with AlphaFold-based screening

The paper introduces an active learning strategy using Thompson sampling to efficiently screen peptide libraries with AlphaFold-based binding predictions, achieving significant improvements over random sampling.

Divergent effects of target protein stabilisation versus overproduction on PROTAC activity

This study compares how stabilizing versus overproducing target proteins affects PROTAC activity using β-catenin as a model.

Loop Plasticity Drives Paralog-Specific Recognition in BET ET Domains

The paper investigates how sequence variations in BET ET domains influence paralog-specific peptide recognition through loop dynamics and conformational changes.

Biophysical Modeling Elucidates Mechanistic Principles for Rational Molecular Glue Design

This paper develops a mathematical framework to analyze molecular glues, showing that strong ternary complex binding affinity is key for performance, with degrader performance limited by catalytic efficiency and target half-life.

FragLite mapping to identify the BRD4 recruitment site of P-TEFb

The paper uses FragLites to map BRD4 recruitment sites on cyclin T2, revealing interactions with CDK9, AFF4, and HIV-1 Tat, and integrates this with biophysical and AlphaFold3 analyses to define the cyclin T-BRD4 interface.

Harnessing FBXO31 with terminal amide-functionalized molecules for targeted protein degradation

This paper demonstrates the use of FBXO31 as an E3 ligase for targeted protein degradation using amidated motifs, showing broader target degradation potential compared to CRBN-based degraders.

The contribution of native protein complexes to targeted protein degradation

This study shows that molecular glue degraders targeting CK1 can co-degrade multiple SACK1 proteins, highlighting the role of protein complex context in targeted protein degradation.

Charged Molecular Glue Discovery Enabled by Targeted Degron Display

The paper discovers a charged molecular glue, c-Glue, through targeted degron display, enabling the development of Molecular Glue Degraders (MGDs) for protein degradation.

Ligand-induced Conformational Plasticity of the CTLH E3 Ligase Receptor GID4

This study designs high-affinity ligands for the E3 ligase GID4 to enable targeted protein degradation, identifying conformational changes and potential degrader structures, though degradation efficacy remains to be optimized.

Assessing the Suitability of Deubiquitylases As Substrates For Targeted Protein Degradation

This study evaluates whether deubiquitylases (DUBs) can be effectively degraded by PROTACs, finding that some DUBs are degradable while others resist degradation due to auto-deubiquitylation or poor proteasome substrate properties.

Reshaping the progranulin/sortilin interaction for targeted degradation of extracellular proteins

This paper develops SORTACs, small molecules that degrade extracellular proteins by hijacking the sortilin/progranulin interaction, showing nanomolar potency against TNFα.

Indazolone-Based Molecular Glue Degraders as a Tunable Platform for Reprogramming Cereblon Substrate Specificity

This paper introduces an indazolone-based platform for CRBN molecular glue degraders, enabling tunable substrate specificity and broad therapeutic potential.

An epigenetic bifunctional that toggles between transactivation and repression

This paper identifies a bifunctional small molecule that can induce both transactivation and repression of gene expression depending on cellular context.