Acta Biomaterialia, Journal Year: 2025, Volume and Issue: unknown
Published: Feb. 1, 2025
Language: Английский
Journal of Medicinal Chemistry, Journal Year: 2025, Volume and Issue: unknown
Published: Feb. 26, 2025
Cyclic GMP-AMP synthase (cGAS), a critical cytosolic DNA sensor initiating innate immune responses in the presence of DNA, is increasingly recognized as promising therapeutic target for ulcerative colitis (UC). Here, we reported design, synthesis, structure-activity relationship exploration and biological evaluation novel class CRBN-recruiting cGAS-targeting PROTAC degraders. Among them, TH35 exhibited most favorable degradation profile, achieving potent selective cGAS, markedly attenuated dsDNA-induced activation cGAS signaling both human murine cells, with minimal cytotoxic effects. In vivo, demonstrated superior efficacy dextran sulfate sodium (DSS)-induced mouse model UC compared to corresponding inhibitor, while also displaying acceptable pharmacokinetic properties. Collectively, first holds promise augmenting anti-inflammatory offers new avenue treating cGAS-driven inflammatory diseases.
Language: Английский
Citations
1
Nucleic Acids Research, Journal Year: 2024, Volume and Issue: 53(D1), P. D1510 - D1515
Published: Sept. 3, 2024
Proteolysis-targeting chimera (PROTAC) is an emerging therapeutic technology that leverages the ubiquitin-proteasome system to target protein degradation. Due its event-driven mechanistic characteristics, PROTAC has potential regulate traditionally non-druggable targets. Recently, AI-aided drug design accelerated development of drugs. However, rational PROTACs remains a considerable challenge. Here, we present updated online database, PROTAC-DB 3.0. In this third version, have expanded database include 6111 (87% increase compared 2.0 version). Additionally, now contains 569 warheads (small molecules targeting protein), 2753 linkers, and 107 E3 ligands recruiting ligases). The number target-PROTAC-E3 ternary complex structures also increased 959. Recognizing importance druggability in design, incorporated pharmacokinetic data To enhance user experience, added features for sorting based on molecular similarity literature publication date. 3.0 accessible at http://cadd.zju.edu.cn/protacdb/.
Language: Английский
Citations
7
Trends in Pharmacological Sciences, Journal Year: 2024, Volume and Issue: unknown
Published: Nov. 1, 2024
Language: Английский
Citations
6
Journal of Cellular and Molecular Medicine, Journal Year: 2025, Volume and Issue: 29(1)
Published: Jan. 1, 2025
ABSTRACT Multiple myeloma (MM) is a haematological lymphoid malignancy marked by significant morbidity due to severe complications. Despite advances in targeted therapies, including proteasome inhibitors and the BCL‐2 inhibitor venetoclax, drug resistance frequently occurs, with underlying mechanisms poorly understood. This study investigates role of lysosome‐associated protein transmembrane 5 (LAPTM5) conferring venetoclax relapsed MM. Using comprehensive analyses publicly available databases experimental validation, we demonstrated that LAPTM5 upregulated enhances autophagy recurrent multiple cells, which key process for cell homeostasis resistance. Mechanistic studies reveal facilitates autophagic flux, linking it cellular catabolic processes essential survival under therapeutic stress. Our findings highlight underexplored functions modulating resistance, demonstrate confers enhancing autophagy, suggesting targeting may provide new avenues overcoming treatment challenges. research underscores potential function as target improving outcomes MM treatment.
Language: Английский
Citations
0
Journal of the American Chemical Society, Journal Year: 2025, Volume and Issue: unknown
Published: Jan. 3, 2025
Proteolysis-targeting chimeras (PROTACs) are dual-functional molecules composed of a protein interest (POI) ligand and an E3 ligase connected by linker, which can recruit POI ligases simultaneously, thereby inducing the degradation showing great potential in disease treatment. A challenge developing PROTACs is design linkers modification ligands to establish multifunctional platform that enhances efficiency antitumor activity. As programmable modifiable nanomaterial, DNA tetrahedron precisely assemble selectively recognize flexibly adjust distance between molecules, making them ideal linkers. Herein, we developed multivalent PROTAC based on tetrahedron, named AS-TD2-PRO. Using as combined modules targeting tumor cells, recognizing ligases, multiple together. We took undruggable target signal transducer activator transcription 3 (STAT3), associated with etiology progression variety malignant tumors, example this study. AS-TD2-PRO two STAT3 recognition demonstrated good enhancing tumor-specific compared traditional bivalent PROTACs. Furthermore, mouse model, superior therapeutic activity was observed. Overall, tetrahedron-driven both serve proof principle for introduce promising avenue cancer treatment strategies.
Language: Английский
Citations
0
Acta Pharmacologica Sinica, Journal Year: 2025, Volume and Issue: unknown
Published: Jan. 7, 2025
Language: Английский
Citations
0
Published: Jan. 1, 2025
It was previously considered that protein knockdown using a combination of zinc finger degron tag and thalidomide analog is impossible in mouse cells, however, EGFP expression as an indicator, we found possible super-degron (SD) with iberdomide or mezigdomide cells. Despite the efficient degradation SD-tagged wild-type PD-1 could not be degraded but human Jurkat cells human-type CEREBLON (CRBNI391V). In mice CRBNI391V, endogenous tagged SD efficiently suppressed T both cultured whole body. addition, comparison treatment anti-PD-1 antibody suggested transient downregulation might prevent cell exhaustion compared to treatment. brain also reduced by pomalidomide crosses brain-blood barrier. These results suggest analogs are effective for vitro vivo knockdown, although some conditional settings required.
Language: Английский
Citations
0
bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown
Published: Jan. 8, 2025
Abstract Background The specificity of the ubiquitination process is mediated by E3 ligases. Discriminating genuine substrates E3s from mere interacting proteins one major challenges in field. We previously developed BioE3, a biotin-based approach that uses BirA-E3 fusions together with ubiquitin fused to low-affinity AviTag obtain site-specific and proximity-dependent biotinylation substrates. proved suitability BioE3 identify targets RING HECT-type Methods experiments were performed HEK293FT U2OS stable cell lines expressing TRIPZ-bio GEF Ub transiently transfected BirA-cereblon (CRBN). Cells seeded using biotin-free media, adding short-biotin pulse. evaluated applicability system CRBN molecular glues western blot confocal microscopy, blocking proteasome bortezomib, inhibiting NEDDylation MLN4924 treating cells pomalidomide. For identification endogenous neosubstrates we analyzed eluates streptavidin pull-downs LC-MS/MS. Analysis which changes significantly upon treatment was done two-sided Student’s t-test. Orthogonal validations histidine pull-down, GFP-trap computational modelling. Results Here demonstrate suitable for multi-protein complex Cullin-RING ligases (CRLs), most utilized targeted protein degradation strategies. Choosing as proof concept, substrate receptors CRL4 ligase, identified both novel pomalidomide treatment, including CSDE1 contains G-loop motif potentially involved binding presence Importantly, observed rearrangement landscape this glue. Conclusions ability detect compare neosubstrates, well how change response treatments, will facilitate target off-target identifications offer broader characterization validation degraders, like PROTACs.
Language: Английский
Citations
0
Nature Microbiology, Journal Year: 2025, Volume and Issue: unknown
Published: Jan. 15, 2025
Language: Английский
Citations
0
Medicinal Research Reviews, Journal Year: 2025, Volume and Issue: unknown
Published: Jan. 21, 2025
ABSTRACT Targeted protein degradation (TPD) has emerged as a significant therapeutic approach for variety of diseases, including cancer. Advances in TPD techniques, such molecular glue (MG) and lysosome‐dependent strategies, have shown substantial progress since the inception first PROTAC 2001. The methodology represents forefront technology, with ongoing evaluation more than 20 clinical trials treatment diverse medical conditions. Two prominent PROTACs, ARV‐471 ARV‐110, are currently undergoing phase III II trials, respectively. Traditional PROTACs encountering obstacles limited binding affinity restricted range E3 ligase ligands facilitating interest (POI) degradation. Covalent medicines offer potential to enhance efficacy by enabling targeting previously considered “undruggable” shallow sites. Strategic alterations allow establish covalent connections particular target proteins, Kirsten rat sarcoma viral oncogene homolog (KRAS), Bruton's tyrosine kinase (BTK), epidermal growth factor receptor (EGFR), well ligases DDB1 CUL4 associated 16 (DCAF16) Kelch‐like ECH‐associated 1 (Keap1). concept also been utilized various new forms degraders, molecule (MG), in‐cell click‐formed proteolysis chimera (CLIPTAC), HaloPROTAC, lysosome‐targeting (LYTAC) GlueTAC. This review focuses on recent advancements degraders beyond examines future directions pertinent this field.
Language: Английский
Citations
0