Protein Degradation and Inhibitors

This study identifies fatty acid promoieties that improve CNS exposure of targeted protein degraders by enhancing pharmacokinetics and BBB permeability.

This study shows that a monovalent MGD can recruit two E3 ligases redundantly to degrade SMARCA2/4, with tunable ligase preference through chemical and genetic modifications.

This paper identifies covalent modulators that target and degrade IRF5 and IRF8, key inflammatory transcription factors, with TH-B10 showing potent and selective degradation of IRF8.

This paper introduces a method called cerebody to detect and enrich endogenous cereblon substrates by targeting C-terminal cyclic imide modifications.

This study develops a small-molecule degrader, XMU-MP-9, that promotes ubiquitination and degradation of K-Ras mutants, including K-RasG12V, by enhancing Nedd4-1 interaction with K-Ras.

The paper identifies 298 protein targets of CRBN-binding molecular glues using a high-throughput affinity purification mass spectrometry workflow and demonstrates a lead compound for the new target PPIL4.

This paper develops PROTACs that cross the blood-tumor barrier by targeting nucleolin, showing anti-glioblastoma efficacy without toxicity.

The paper optimizes and evaluates two cell-based assays for degrader discovery, finding that the signal rescue assay reliably identifies active degraders and filters out non-specific compounds.

This paper introduces a platform for discovering molecular glue degraders by engineering effector proteins to enable systematic identification of new small molecule degraders targeting GSPT1.

The paper identifies PRLX-93936 and BMS-214662 as molecular glues that use TRIM21 to degrade nucleoporins, leading to cell death and potential therapeutic applications in TRIM21-high cancers.

The paper predicts over 1,400 CRBN-compatible β-hairpin G-loop proteins and validates 22 neosubstrates, redefining rules for molecular glue-induced degradation.

This study develops LCK-targeting molecular glues that overcome resistance to kinase inhibitors in T-ALL by inducing CRBN-dependent degradation of LCK.

This paper identifies a covalent degradative handle that can be transplanted onto various protein-targeting ligands to induce degradation of their targets, enabling modular degrader design.

The paper identifies a small molecule that acts as a molecular glue degrader for CDO1 by recruiting it into the VHL E3 ligase complex, leading to its degradation.

This study develops MA191, a PROTAC degrader of FLT3-ITD, which overcomes resistance in AML cells by rapidly degrading the mutant protein and shows efficacy in vivo.

This paper designs and tests sEH-PROTACs to degrade soluble epoxide hydrolase, identifying PROTAC 23 as effective in degrading sEH in human macrophages.

This paper introduces a cell-based platform to assess PROTACs targeting NUDT5, identifying a VHL-dependent degrader despite poor in vitro binding and showing CRBN-dependent degraders are ineffective.

This paper introduces an in-cell method to evaluate E3 ligases for targeted protein degradation by conjugating neo-substrates via click chemistry.

The paper introduces a chemical-genetic platform called SLIP to identify actionable sites on effector proteins for targeted protein degradation.

This paper develops a scAb-AID2 system for conditional protein degradation without requiring degron tags, demonstrating its effectiveness in human and C. elegans cells.

The paper determines cryo-EM structures of IMiDs in full CRL4CRBN complexes, revealing a cryptic interfacial pocket that enhances IMiD efficacy and neosubstrate specificity.

This paper develops LIPTACs, LDLR-targeting chimeras that enhance lysosomal delivery and cytotoxicity for cancer treatment by combining eTPD and ADC strategies.

This study designs and tests PROTACs targeting β-tubulin, showing two compounds effectively degrade tubulin in cells.

This study develops heterobifunctional protein binders that selectively kill specific cell types by leveraging the abundance of FKBP12, demonstrating enhanced efficacy through cellular enrichment.

This study identifies a new IMiD-independent drug targeting SALL4's ZFC4 domain, leading to significant tumor growth inhibition in vivo.

The paper introduces two ultrasmall chemogenetic tags, mgTag and cTag, which enable group-transfer reactions to append moieties to proteins, demonstrating their utility in cell signaling and proximity induction.

The paper demonstrates that multivalent ligand-protein interactions using PolyTACs can degrade transmembrane proteins without lysosome-targeting receptors.

This study develops an antiviral PROTAC targeting SARS-CoV-2 MPro using an allosteric warhead, showing LLP019 can degrade MPro and inhibit viral variants in infected cells.

This study develops PSMA-guided PROTACs for prostate cancer, showing they selectively degrade target proteins in PSMA-overexpressing cells and improve therapeutic effects in vivo.

This study evaluates bifunctional ER degraders with different ubiquitin ligase ligands, finding that pan-IAP antagonists enhance ER degradation and induce TNF-dependent cell death more effectively than existing therapies.