Protein Degradation and Inhibitors

This paper develops a miniaturized Direct-to-Biology platform for rapid PROTAC degrader synthesis and screening, identifying potent sEH degraders with subnanomolar activity.

The paper evaluates AlphaFold's ability to predict PROTAC-mediated protein interfaces and finds it struggles with small interfaces, impacting PROTAC design.

This paper develops a first-in-class RIPK1 degrader, LD4172, which enhances antitumor immunity by promoting immunogenic cell death and sensitizing tumors to anti-PD1 therapy.

This paper demonstrates a method to enhance protein degradation by recruiting E3 ligases to specific protein sites, showing improved degradation of target proteins and informing PROTAC development.

This study uses kinetic Monte-Carlo simulations to model protein-protein interactions in PROTAC-induced ternary complex formation, showing that cooperativity affects association into native-like configurations.

This study develops a kinetic scout approach to accelerate targeted protein degrader development by tuning ligand residence time through chemical proteomics and mechanistic assays.

This study synthesizes Biguanide-PROTACs and evaluates their activity on pancreatic cancer cells, finding structure-permeability-activity relationships and some AMPK activation.

The paper introduces a method to identify direct protein substrates of small-molecule degraders using degradome analysis and mass spectrometry.

The paper identifies CRBN-dependent WEE1 molecular glue degraders through combinatorial library screening and medicinal chemistry, providing structural insights into kinase selectivity.

This study identifies acepromazine as a compound that selectively degrades multimeric proteins via TRIM21 activation, offering a new strategy for targeting disease-related protein assemblies.

The paper introduces CRBNmidi, a Cereblon construct that enables high-resolution structural and biophysical studies of degraders without requiring DDB1 co-expression.

The paper solves cryo-EM structures of a degrader-mediated complex to reveal structural insights into target protein ubiquitination mechanisms.

CYpHER is a targeted protein degradation technology that uses pH-dependent release and the transferrin receptor to deliver drugs to endolysosomes, demonstrating potency and durability in vitro and in vivo.

The paper develops bivalent molecules that convert kinase inhibitors into activators of proapoptotic genes, achieving selective killing of DLBCL cells with low cytotoxicity.

This paper develops next-generation sEH-targeting PROTACs with improved potency and stability, showing effective degradation in mouse tissues.

This paper introduces TransTACs, a method for degrading membrane proteins by redirecting them to lysosomal degradation using the transferrin receptor, showing high efficiency across various protein types.

This study evaluates how electrophilic modifications to JQ1 affect DCAF16 trans-labeling and BRD4 degradation, showing a correlation between warhead exposure and degradation efficiency.

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.

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.

This study shows BET inhibition reduces E6 and E7 expression in HPV-16 HNSCC, with variable effects on p53 and Rb, and induces G1 arrest and apoptosis.

This study develops PROTACs to degrade YAP, showing effective tumor suppression in cancer cell lines and xenograft models.

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 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 study identifies FBXO22 as an E3 ligase that supports ligand-induced protein degradation through PROTACs, expanding the toolkit for targeted protein degradation.

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.