Protein Degradation and Inhibitors

This study designs and optimizes covalent VHL-targeted sulfonyl fluoride PROTACs that degrade BRD4 and androgen receptor without linker optimization.

This paper develops a single-domain antibody-based protein degrader that enhances proteasomal and lysosomal degradation of α-synuclein in synucleinopathy models.

The paper discusses discrepancies in conclusions about arylidene-indolinones' mechanism of action, suggesting possible explanations for conflicting findings on their role as DCAF11 ligands and autophagy-tethering compounds.

The paper describes the development of new antibodies that enhance Wnt signaling through targeted protein degradation by sequestering E3 ligases.

The paper identifies that BET inhibitor efficacy depends on the INTAC complex's auxiliary module, which interacts with the RACK7/ZMYND8-KDM5C complex to remove H3K4 methylation, thereby restoring sensitivity to BET inhibitors through WDR5 degradation.

This study develops KH12, a METTL3 degrader, showing potent anti-leukemia and anti-gastric cancer effects through m6A-dependent and -independent mechanisms.

This study identifies a covalent recruiter against SKP1 for PROTAC-based protein degradation, demonstrating its efficacy in degrading BRD4 and androgen receptor via the SCF complex.

This paper introduces a new CRBN construct for efficient binder discovery, showing it outperforms existing constructs in binding and production, and applies it to identify potent CRBN binders from a large compound library.

This paper develops SNAP-PROTACs to induce degradation of SNAP-fusion proteins, enabling selective depletion and functional analysis of target proteins.

The paper develops chemical tools and probes for the Gid4 subunit of the human CTLH E3 ligase complex, achieving sub-100 nM binding affinity for further study.

This paper designs and synthesizes Chk1 degraders using a promiscuous kinase binder and thalidomide, showing concentration-dependent reduction of Chk1 in A375 cells.

This study identifies SR-4835 as a CDK12 inhibitor that promotes cyclin K degradation via the proteasome by recruiting the CDK12-cyclin K complex to the CUL4-RBX1-DDB1 ubiquitin ligase complex.

This paper introduces a novel GR degrader, KH-103, which selectively degrades glucocorticoid receptors and shows improved efficacy over existing inhibitors.

This paper develops IGF2-based LYTACs for lysosomal degradation of extracellular and transmembrane proteins, showing enhanced in vitro effects compared to anti-PD-L1 antibodies.

This study identifies how BET inhibitors alter the BRD4 interactome via the ubiquitin proteasome system, revealing complex mechanisms and potential new therapeutic strategies.

The paper identifies a cysteine-reactive small molecule degrader of SARS-CoV-2 nsp14, showing it causes protein aggregation, depletion, and stress granule formation in cells.

The paper presents a computational method to predict PROTAC-compatible protein-protein interfaces using docking and scoring techniques, achieving high accuracy in benchmark tests.

This paper benchmarks PROTAC docking and virtual screening tools to evaluate their ability to predict ternary complexes and distinguish active from inactive PROTACs.

The paper designs EndoTags to trigger endocytosis and degradation of target proteins, enabling tissue-specific targeting and therapeutic applications.

The paper develops PrePROTAC, an interpretable machine learning model to predict PROTAC-induced protein degradation targets, identifying over 600 novel understudied proteins and proposing PROTAC compounds for Alzheimer's disease targets.

This study demonstrates a method to degrade native proteins by directly recruiting them to the proteasome without requiring ubiquitylation.

This paper develops cell-based assays to monitor PROTAC degradation kinetics and ternary complex formation, revealing that ternary complex stability is critical for PROTAC efficiency.

This paper introduces a computational method for in-silico PROTAC design and evaluation, demonstrating its ability to predict PROTAC binding modes and thermodynamics for known and novel target systems.

This paper introduces a method to degrade phospho-14-3-3-binding-motif proteins using a ubiquitin-proteasome system, demonstrating its efficiency and specificity for studying these proteins.

The paper benchmarks six MYB inhibitors using a nascent transcriptomics assay, revealing partial specificity, off-target activity, and mixed agonism-antagonism effects.

This paper identifies AK59 as a molecular glue degrader for STING, showing HERC4 is the key E3 ligase for its degradation and demonstrating efficacy against STING mutations.

This paper develops a scalable method to identify E3-specific degraders by tracing substrate receptor abundance changes induced by pharmacological auto-degradation.

The paper develops a method to restrict the search space for PROTAC-mediated protein-protein interactions using a cyclic coordinate descent algorithm, showing the global minimum corresponds to native-like conformations.

The paper identifies functional E3 ligase hotspots and resistance mechanisms to small-molecule degraders using haploid genetics and deep mutational scanning.

This paper establishes an in-silico rationale for molecular glue design by analyzing a known case and discusses its application in designing novel molecular glues using AI techniques.