Aug 2026· Bioorganic chemistry (Print)· Vol 181, pp.
110328
· 0 citations· 35 references
Medicine
TL;DR
This work reports the first ligand-directed chemical strategy that converts transient PROTAC-mediated ternary complex formation into binary target recognition via post-translational chemical modification of an E3 ligase, and believes it could provide a platform for next-generation targeted protein degraders to overcome the current limitation of PROTAC approach.
Abstract
Targeted protein degradation (TPD) has emerged as a powerful therapeutic strategy, with proteolysis-targeting chimeras (PROTACs) leading efforts to address previously undruggable targets. However, PROTACs face challenges such as low bioavailability and poor pharmacokinetic properties which limit their biological applications. Here, we report a strategy termed post-translational chemical modification targeting chimera (PTcM-TAC), which integrates ligand-directed chemistry into the PROTAC framework to achieve sustained target protein degradation through covalent modification of E3 ligases. PTcM-TAC incorporates an electrophilic dibromophenyl benzoate warhead into the linker connecting the E3 ligase ligand and the protein-of-interest (POI) ligand, enabling selective transfer of the POI ligand onto the recruited E3 ligase while releasing the E3-binding moiety. Mechanistic studies, including LC-MS/MS peptide mapping, pull-down assays, and structural modeling, demonstrated site-selective modification of CRBN by the PTcM-TAC. The resulting ligand-labeled E3 ligase enables sustained pseudo-catalytic target recognition through a simplified binary interaction, thereby maintaining degradation activity even after compound washout. Furthermore, we successfully applied the PTcM-TAC strategy to another representative E3 ligase, von Hippel-Lindau (VHL), which exhibited substantially sustained degradation activity compared with conventional PROTACs. To our knowledge, PTcM-TAC represents the first ligand-directed chemical strategy that converts transient PROTAC-mediated ternary complex formation into binary target recognition via post-translational chemical modification of an E3 ligase. We believe that PTcM-TAC could provide a platform for next-generation targeted protein degraders to overcome the current limitation of PROTAC approach.
This review summarizes recent advances in chemical protein degradation strategies for neurodegenerative disorders and highlights potential future perspectives of multifunctional PROTACs for therapeutic development.
Pasquale Degennaro, Imane Ghafir El Idrissi, Rosa Purgatorio et al.· Pharmaceuticals· 0 citations
Proteolysis-targeting chimeras (PROTACs) are currently constrained by a reliance on ubiquitously expressed E3 ligases, which compromises tumor selectivity and raises toxicity risks. Here, we identified KLHL12 as a potentially tumor-selective E3 ligase and reported the development of the first-in-class KLHL12-recruiting PROTACs. Guided by a structure-based macrocyclization strategy, we obtained a high‑affinity cyclic peptide, cp4, as a KLHL12‑binding ligand and constructed novel PROTACs against oncogenic BRD4 and EGFR. The optimal compound k12bp-1 achieved tumor-selective BRD4(L) degradation in A549 cells, significantly inhibiting cell proliferation and driving cell apoptosis while sparing normal cells. It demonstrated robust in vivo antitumor efficacy in A549 xenograft mouse models without observable systemic toxicity. Collectively, this work established KLHL12 as a promising tumor‑selective E3 ligase and provided a KLHL12-recruiting PROTAC platform for cancer therapy.
Shicheng Xu, Xian Zhang, Shun-Bo Hu et al.· Angewandte Chemie· 0 citations
An overview of the developmental trajectory of the TPD field is provided and how diverse modalities can be leveraged to address intracellular, membrane-associated, and extracellular protein targets are discussed.
Yu-bo Zhang, Junwei Fu, Yue Liu et al.· Acta Pharmacologica Sinica· 0 citations
Targeted protein degradation (TPD) represents a promising approach for eliminating disease-causing proteins beyond traditional inhibition. However, the reliance on a limited number of E3 ligases remains a major bottleneck. FEM1B, an E3 ligase substrate receptor with multiple substrate-recognition modes, represents an attractive but underexplored TPD platform. In this study, through a structure-guided approach exploiting the spatial proximity between a druggable C-degron-binding pocket and a second binding site containing a reactive cysteine, we developed FL47, a dual-site ligand that combines extensive noncovalent interactions with targeted covalent engagement. FL47 exhibits submicromolar affinity, robust cellular target engagement, and markedly reduced cytotoxicity relative to previously reported covalent recruiters. We further applied FL47 in the development of FEM1B-based PROTACs and incorporated a chemical endocytic prodrug strategy that markedly enhanced degradation activity. This work introduces a novel dual-site binding strategy for E3 ligase ligand discovery and broadens the potential toolbox for TPD applications.
Ling-xiang Xu, Ruyi Huang, Yuying Ma et al.· Journal of Medicinal Chemist...· 0 citations
Targeted protein degradation (TPD) has emerged as a powerful strategy to eliminate disease-relevant proteins, yet current approaches remain largely constrained to hijacking ubiquitin ligases. We previously introduced ByeTACs, bifunctional molecules that directly recruit proteins to the proteasome for E-ligase independent degradation. Here, we report "Truly" degraders, a new class of dual-mechanism molecules that combine a ligand for the proteasomal receptor Rpn13 with a ligand for cereblon (CRBN) to simultaneously engage both ubiquitin-independent and ubiquitin-dependent degradation pathways. Structure-guided design identified an optimal linker length that supports efficient substrate processing, with the PEG4 derivative (Truly-4) inducing robust depletion of both Rpn13 and CRBN in several cancer cell types. Remarkably, Truly-4 is the first noncovalent small molecule shown to degrade full-length Rpn13, a target previously approached using covalent or domain-restricted strategies. Mechanistic studies confirmed that degradation of Rpn13 proceeds via CRBN-dependent E3 ligase activity, whereas CRBN degradation occurs through an E-ligase independent process, consistent with a ByeTAC mechanism. Importantly, Truly-4 induces selective cytotoxicity in hematologic and solid cancer cell lines but not in healthy cells, despite comparable Rpn13 depletion, indicating that dual degradation can uncouple target engagement from toxicity. These findings establish a generalizable framework for engineering bifunctional degraders that program the proteasome to execute parallel degradation mechanisms and highlight proteasome receptors as druggable nodes for selective destruction of disease-relevant proteins.
Cody A. Loy, Shawn E Vinogradsky, Darci J. Trader· Journal of the American Chem...· 0 citations
Targeted protein degradation is a powerful pharmacological strategy that harnesses the ubiquitin proteasome system to eliminate disease-relevant proteins, including otherwise undruggable proteins1. Here we report an unbiased and broadly applicable platform for the systematic discovery of molecular glues across diverse E3 ligases. Using multiplexed mass spectrometry-based chemical screening, we identified M12, a molecular glue that reprogrammes the E3 ligase DCAF11 to degrade DDX18. Mechanistically, M12 functions as a prodrug that is activated through glutathione S-transferase-mediated glutathionylation. The glutathione moiety binds to an evolutionary conserved glutathione-binding site on DCAF11, and the exposed M12 moiety facilitates neo-substrate recruitment. We demonstrate that this glutathione-dependent mechanism readily enables targeted degradation of a range of proteins. Collectively, these findings establish that metabolically activated compounds can redirect E3 ligase function, thereby expanding the scope of targeted protein degradation and chemically induced proximity.
Hojong Yoon, Franziska Wachter, Katharine A Barrett et al.· Nature· 1 citation
