January 2024 Highlights Methotrexate-based PROTACs as DHFR-specific chemical probes Anti-tumor immunotherapy using engineered bacterial outer membrane vesicles fused to lysosome-targeting chimeras mediated by transferrin receptor Discovery and Preclinical Pharmacology of NX-2127, an Orally Bioavailable Degrader of Bruton’s Tyrosine Kinase with Immunomodulatory Activity for the Treatment of Patients with B Cell Malignancies Proteolysis-targeting chimeras with reduced off-targets Selective CK1α degraders exert antiproliferative activity against a broad range of human cancer cell lines Ubiquitin-Derived Fragment as a Peptide Linker for the Efficient Cleavage of a Target Protein from a Degron Design, Synthesis, and In Vitro and In Vivo Evaluation of Cereblon Binding Bruton’s Tyrosine Kinase (BTK) Degrader CD79b Targeted Antibody–Drug Conjugates JAK1/JAK2 degraders based on PROTAC for topical treatment of atopic dermatitis Discovery of a PROTAC degrader for METTL3-METTL14 complex A small molecule VHL molecular glue degrader for cysteine dioxygenase 1 From Thalidomide to Rational Molecular Glue Design for Targeted Protein Degradation Discovery of Novel PDEδ Autophagic Degraders: A Case Study of Autophagy-Tethering Compound (ATTEC) Cereblon-Based Bifunctional Degrader of SOS1, BTX-6654, Targets Multiple KRAS Mutations and Inhibits Tumor Growth Development of sulfonyl fluoride chemical probes to advance the discovery of cereblon modulators† Discovery of Potent SOS1 PROTACs with Effective Antitumor Activities against NCI-H358 Tumor Cells In Vitro/In Vivo Design, Synthesis, and Biological Evaluation of Potent and Selective PROTAC Degraders of Oncogenic KRASG12D PROTACs Targeting BRM (SMARCA2) Afford Selective In Vivo Degradation over BRG1 (SMARCA4) and Are Active in BRG1 Mutant Xenograft Tumor Models Development of a GC-376 Based Peptidomimetic PROTAC as a Degrader of 3-Chymotrypsin-like Protease of SARS-CoV-2 Design and Evaluation of PROTACs Targeting Acyl Protein Thioesterase 1 Journey of Von Hippel-Lindau (VHL) E3 ligase in PROTACs design: From VHL ligands to VHL-based degraders Discovery of the cereblon-recruiting tubulin PROTACs effective in overcoming Taxol resistance in vitro and in vivo Design, synthesis, and evaluation of VHL-based EZH2 degraders for breast cancer Degradation by Design: New Cyclin K Degraders from Old CDK Inhibitors DCAF1-based PROTACs with activity against clinically validated targets overcoming intrinsic- and acquired-degrader resistance Co-opting the E3 ligase KLHDC2 for targeted protein degradation by small molecules Proteolysis-targeting chimeras with reduced off-targets November 2023 Highlights Design and Synthesis of Novel Cereblon Binders for Use in Targeted Protein Degradation Identification of Small Molecule Inhibitors and Ligand Directed Degraders of Calcium/Calmodulin Dependent Protein Kinase Kinase 1 and 2 (CaMKK1/2) Cooperatively designed aptamer-PROTACs for spatioselective degradation of nucleocytoplasmic shuttling protein for enhanced combinational therapy† Discovery of Potent and Selective WDR5 Proteolysis Targeting Chimeras as Potential Therapeutics for Pancreatic Cancer Molecular glues targeting GSPT1 in cancers: A potent therapy Discovery of a selective TC-PTP degrader for cancer immunotherapy† Kinetic Modeling of PROTAC-Induced Protein Degradation Discovery of a Drug-like, Natural Product-Inspired DCAF11 Ligand Chemotype Covalent PROTAC design method based on a sulfonyl pyridone probe† Insulin-like Growth Factor 2 (IGF2)-Fused Lysosomal Targeting Chimeras for Degradation of Extracellular and Membrane Proteins Covalent LYTAC Enabled by DNA Aptamers for Immune Checkpoint Degradation Therapy Leveraging Ligand Affinity and Properties: Discovery of Novel Benzamide-Type Cereblon Binders for the Design of PROTACs Recent progress in degradation of membrane proteins by PROTACs and alternative targeted protein degradation techniques Chemical Specification of E3 Ubiquitin Ligase Engagement by Cysteine-Reactive Chemistry Integrated Direct-to-Biology Platform for the Nanoscale Synthesis and Biological Evaluation of PROTACs Glutathione-responsive PROTAC for targeted degradation of ERα in breast cancer cells Click Chemistry and Targeted Degradation: A Winning Combination for Medicinal Chemists? Rapid PROTAC Discovery Platform: Nanomole-Scale Array Synthesis and Direct Screening of Reaction Mixtures Discovery of proteolysis-targeting chimera targeting undruggable proteins using a covalent ligand screening approach Targeted Protein Degradation of Histone Deacetylases by Hydrophobically Tagged Inhibitors Discovery of Ligands for TRIM58, a Novel Tissue-Selective E3 Ligase Kinetic Modeling of PROTAC-Induced Protein Degradation Genetic retargeting of E3 ligases to enhance CAR T cell therapy Discovery of Molecular Glue Degraders via Isogenic Morphological Profiling Discovery of LWY713 as a potent and selective FLT3 PROTAC degrader with in vivo activity against acute myeloid leukemia October 2023 Highlights Chemical Specification of E3 Ubiquitin Ligase Engagement by Cysteine-Reactive Chemistry Targeted Protein Degradation Mediated by Genetically Engineered Lysosome-Targeting Exosomes ATNC: Versatile Nanobody Chimeras for Autophagic Degradation of Intracellular Unligandable and Undruggable Proteins Altering the Cleaving Effector in Chimeric Molecules that Target RNA Enhances Cellular Selectivity Conjugation with glucagon like peptide-1 enables targeted protein degradation Discovery of a SHP2 Degrader with In Vivo Anti-Tumor Activity Expanding PROTACtable genome universe of E3 ligases Discovery of highly potent and selective KRASG12C degraders by VHL-recruiting PROTACs for the treatment of tumors with KRASG12C-Mutation Elucidating the cellular determinants of targeted membrane protein degradation by lysosome-targeting chimeras Rational Screening for Cooperativity in Small-Molecule Inducers of Protein–Protein Associations Rational Design of Bioorthogonally Activatable PROTAC for Tumor-Targeted Protein Degradation Identification of KLHDC2 as an efficient proximity-induced degrader of K-RAS, STK33, β-catenin, and FoxP3 Methotrexate-based PROTACs as DHFR-specific chemical probes Targeting cancer with small molecule pan-KRAS degraders September 2023 Highlights Discovery of ERD-3111 as a Potent and Orally Efficacious Estrogen Receptor PROTAC Degrader with Strong Antitumor Activity Activity-based profiling of cullin–RING E3 networks by conformation-specific probes Development and Applications of Chimera Platforms for Tyrosine Phosphorylation PROTAC chemical probes for histone deacetylase enzymes Incorporating a β-hairpin sequence motif to increase intracellular stability of a peptide-based PROTAC Central Nervous System Targeted Protein Degraders Development of Liposome Systems for Enhancing the PK Properties of Bivalent PROTACs Targeted Lysosomal Degradation of Secreted and Cell Surface Proteins through the LRP-1 Pathway Discovery of novel flavonoid-based CDK9 degraders for prostate cancer treatment via a PROTAC strategy PROTAC for agriculture: learning from human medicine to generate new biotechnological weed control solutions Degradation of Cyclin-Dependent Kinase 9/Cyclin T1 by Optimized Microtubule-Associated Protein 1 Light Chain 3 Beta-Recruiting Coumarin Analogs Design principles for cyclin K molecular glue degraders Mammalian autophagosomes form from finger-like phagophores Discovery of ARD-1676 as a Highly Potent and Orally Efficacious AR PROTAC Degrader with a Broad Activity against AR Mutants for the Treatment of AR + Human Prostate Cancer VHL-Modified PROteolysis TArgeting Chimeras (PROTACs) as a Strategy to Evade Metabolic Degradation in In Vitro Applications Development of Potent and Selective Coactivator-Associated Arginine Methyltransferase 1 (CARM1) Degraders Exploring the target scope of KEAP1 E3 ligase-based PROTACs Recent Progress on Microtubule Degradation Agents Design, Synthesis, and Biological Evaluation of Proteolysis-Targeting Chimeras as Highly Selective and Efficient Degraders of Extracellular Signal-Regulated Kinase 5 Targeted protein degradation in drug development: Recent advances and future challenges Chemical Specification of E3 Ubiquitin Ligase Engagement by Cysteine-Reactive Chemistry Proteomic approaches advancing targeted protein degradation Structural Optimization of Decoy Oligonucleotide-Based PROTAC That Degrades the Estrogen Receptor Unlocking DCAFs To Catalyze Degrader Development: An Arena for Innovative Approaches Photoactivated Protein Degrader for Optical Control of Synaptic Function Defining E3 ligase–substrate relationships through multiplex CRISPR screening Selective Protein of Interest Degradation through the Split-and-Mix Liposome Proteolysis Targeting Chimera Approach Lysosome and related protein degradation technologies Click Chemistry and Targeted Degradation: A Winning Combination for Medicinal Chemists? Unraveling the diversity of molecular glue degraders August 2023 Highlights The midnolin-proteasome pathway catches proteins for ubiquitination-independent degradation Discovery of X10g as a selective PROTAC degrader of Hsp90α protein for treating breast cancer Structural snapshots along K48-linked ubiquitin chain formation by the HECT E3 UBR5 PROTAC for agriculture: learning from human medicine to generate new biotechnological weed control solutions Targeted Degradation of CDK4/6: An Innovative Approach to Overcoming Cancer Drug Resistance Discovery of a First-in-Class Degrader for the Lipid Kinase PIKfyve Targeted Protein Degradation: Advances, Challenges, and Prospects for Computational Methods The application of PROTAC in HDAC An E3 ligase network engages GCN1 to promote the degradation of translation factors on stalled ribosomes Molecular mechanism for activation of the 26S proteasome by ZFAND5 Identification of KLHDC2 as an efficient proximity-induced degrader of K-RAS, STK33, β-catenin, and FoxP3 Second-Generation AUTACs for Targeted Autophagic Degradation Design, synthesis, and evaluation of BTK-targeting PROTACs with optimized bioavailability in vitro and in vivo† Opportunities and challenges of protein-based targeted protein degradation Development of a Highly Potent and Selective Degrader of LRRK2
