Protein Degradation and Inhibitors

This study develops electrophilic degraders using SNAr chemistry, enabling selective protein degradation without requiring a defined E3 ligase recruiter.

A single small molecule degrader targets 13 out of 17 prevalent oncogenic KRAS alleles, inhibiting growth of KRAS-driven cancer cell lines and inducing tumour regression in vivo.

This paper introduces DNA-templated PROTACs (DTACs) that enable precise spatial control over protein degradation, showing enhanced selectivity and potency in degrading the CyclinD1-CDK4/6 complex.

The paper presents a machine-learning pipeline to predict PROTAC degradation potential using compound fingerprints and a graph neural network, achieving better performance than existing methods.

The paper shows that BET bromodomain inhibition does not repress estrogen receptor oncogenic targets due to transcriptional coactivator cooperativity.

This study computationally models PROTAC-induced protein dynamics to explain variation in degradation potency despite identical warheads.

The paper combines AID2 and BromoTag degron systems to enhance protein depletion, demonstrating their effectiveness in suppressing DNA replication by co-depleting ORC1 and CDC6.

This study develops small molecule degraders of the dengue virus envelope protein, demonstrating their ability to induce proteosome-mediated degradation and providing a foundation for antiviral drug development.

This study develops a small molecule, MC-1, that selectively degrades EP300 over CREBBP, revealing factors governing paralogue-specific degradation and its impact on cancer cell proliferation.

This study introduces lysineless HiBiT-RR and nLucK0 tagging systems to reduce degradation artifacts in monitoring protein degradation, showing HiBiT-RR retains sensitivity and nLucK0 shows different degradation patterns than nLucWT.

This paper introduces a rapamycin-induced proximity assay (RiPA) to identify effective E3 ligase-target pairs for PROTAC development, demonstrating its ability to predict degradation capabilities.

This study maps the acetyl lysine machinery interactions and identifies MAPKAPK2 as a factor contributing to resistance to BET bromodomain inhibitors in melanoma.

This paper introduces bioPROTACs, a genetic tool to control CAR T cell signaling by degrading specific proteins, demonstrating its effectiveness in inhibiting CAR signaling in human T cells.

This paper describes a targeted protein degradation strategy using UNC8732 to recruit FBXO22 for NSD2 degradation, leading to growth suppression and reversal of drug resistance in leukemia cells.

This study shows that the natural half-life of a target protein significantly affects degradation by degrader agents and highlights confounding factors in screening for protein degraders.

This paper introduces P-NADs, a ubiquitin-independent protein degradation method using PUX-adaptor proteins and nanobodies, demonstrating their efficacy in human cells and potential for therapeutic applications.

The paper evaluates the impact of PROTAC valency on hook effects, showing that trivalent PROTACs do not eliminate the hook effect but may alter its dynamics.

This paper identifies a covalent degrader, EN83, that targets and degrades β-catenin by covalently binding to four cysteine residues, demonstrating a strategy to overcome the 'undruggable' challenge of transcription factors.

The paper describes a modular method to generate PROxAb Shuttles by conjugating PROTAC-binding VHHs to antibodies, enabling targeted protein degradation and bispecific antibody creation.

The paper introduces PFI-7, a chemical probe that inhibits GID4 Pro/N-degron interactions, revealing non-degradative roles of the CTLH complex in human cells.

The paper develops JQ1-alkenyl oxindole conjugates that degrade BRD4 via the ubiquitin-proteasome system and recruits CRL4DCAF11, identifying HL435 as a potent antitumor lead.

This study identifies a covalent handle that enables the degradation of multiple protein targets when appended to protein-targeting ligands.

The paper analyzes conformational dynamics in PROTAC-induced protein degradation using crystal structures and mathematical modeling, finding that ternary complex rigidity does not enhance degradation and that salt bridges may improve efficiency.

This study identifies rapid resistance to BET inhibitors in glioblastoma mediated by FGFR1 and shows that co-targeting BET and FGFR1 synergizes to reduce tumor growth.

This paper discovers a first-in-class PROTAC degrader for G9a/GLP, showing effective degradation and superior anticancer activity compared to existing inhibitors.

This paper introduces a computational pipeline using AlphaFold2 to prioritize protein-protein binding candidates from high-throughput libraries and identify binding epitopes.

This paper develops an orally bioavailable PROTAC degrader of mSWI/SNF ATPases for prostate cancer and identifies resistance mechanisms through long-term treatment.

The paper describes the development of genetically encodable LYTACs (GELYTACs) for targeted protein degradation using engineered T-cells, showing efficacy in secreting and delivering the therapeutics.

PROTACable automates PROTAC design using 3-D modeling and deep learning to predict activity of newly designed PROTACs.

This paper evaluates a dual BCL-xL/BCL-2 degrader, 753b, showing it effectively reduces tumor viability and growth in SCLC models while avoiding platelet toxicity seen with navitoclax.