Trends in Pharmacological Sciences, Год журнала: 2023, Номер 44(11), С. 743 - 745
Опубликована: Окт. 12, 2023
Язык: Английский
bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown
Опубликована: Сен. 15, 2024
Targeted protein degradation and induced proximity refer to strategies that leverage the recruitment of proteins facilitate their modification, regulation or degradation. As prospective design glues remains challenging, unbiased discovery methods are needed unveil hidden chemical targets. Here we establish a high throughput affinity purification mass spectrometry workflow in cell lysates for identification molecular glue By mapping targets 20 CRBN-binding glues, identify 298 demonstrate utility enrichment identifying novel overlooked using established methods. We use computational estimate target confidence perform biochemical screen lead compound new non-ZF PPIL4. Our study provides comprehensive inventory chemically recruited CRBN delivers robust scalable drug-induced interactions lysates.
Язык: Английский
Процитировано
6
European Journal of Medicinal Chemistry, Год журнала: 2024, Номер 267, С. 116168 - 116168
Опубликована: Фев. 1, 2024
Язык: Английский
Процитировано
5
Journal of Medicinal Chemistry, Год журнала: 2024, Номер 67(6), С. 4804 - 4818
Опубликована: Март 11, 2024
Proteolysis-targeting chimera (PROTAC) is a powerful technology that can effectively trigger the degradation of target proteins. The intricate interplay among various factors leads to heterogeneous drug response, bringing about significant challenges in comprehending mechanisms. Our study applied data-independent acquisition-based mass spectrometry multidimensional proteome profiling PROTAC (DIA-MPP) uncover efficacy and sensitivity compound. We profiled signal transducer activator transcription 3 (STAT3) degrader six leukemia lymphoma cell lines under multiple conditions, demonstrating pharmacodynamic properties downstream biological responses. Through comparison between sensitive insensitive lines, we revealed STAT1 be regarded as biomarker for STAT3 degrader, which was validated cells, patient-derived organoids, mouse models. These results set an example comprehensive description response exploration.
Язык: Английский
Процитировано
4
RSC Medicinal Chemistry, Год журнала: 2025, Номер unknown
Опубликована: Янв. 1, 2025
As the field of targeted protein degradation has advanced, it expanded beyond traditional recruitment to E3 substrate receptors new approaches involving a variety other components within ubiquitin proteasome system.
Язык: Английский
Процитировано
0
Current Issues in Molecular Biology, Год журнала: 2025, Номер 47(3), С. 163 - 163
Опубликована: Фев. 27, 2025
Ubiquitin-specific protease 32 (USP32), a deubiquitylating enzyme that controls the ubiquitin process, is overexpressed in multiple cancers and serves as promising therapeutic target for cancer therapy. Drugs targeting ferroptosis have exhibited anticancer activity. Lycobetaine (LBT), natural alkaloid, holds promise against various cancers, yet its specific targets mechanisms remain unclear. In this study, we show LBT induced lung squamous cell carcinoma (LUSC) cells, accompanied by glutathione depletion accumulation of lipid peroxidation, malondialdehyde, ferrous iron. Mechanistically, drug affinity responsive stability-based mass spectrometry analysis, molecular dynamics simulations, cellular thermal shift assay confirmed USP32 potential LUSC cells. Moreover, strong interaction between nuclear factor erythroid 2-related 2 (NRF2) was found via immunoprecipitation–mass co-immunoprecipitation. addition, ubiquitination results demonstrated treatment significantly increased NRF2 degradation USP32. Importantly, overexpression effectively attenuated effects on proliferation orthotopic xenografts, administration inhibited tumor growth metastasis USP32–NRF2 signaling axis. Taken together, these data suggest exerts inhibiting USP32-mediated deubiquitination to induce may serve prospective USP32-targeting agent treatment.
Язык: Английский
Процитировано
0
Journal of Pharmaceutical and Biomedical Analysis, Год журнала: 2025, Номер unknown, С. 116829 - 116829
Опубликована: Март 1, 2025
Язык: Английский
Процитировано
0
SLAS DISCOVERY, Год журнала: 2023, Номер 29(2), С. 100136 - 100136
Опубликована: Дек. 15, 2023
Molecular glues are small molecules, typically smaller than PROTACs, and usually with improved physicochemical properties that aim to stabilise the interaction between two proteins. Most often this approach is used improve or induce an target E3 ligase, but other interactions which increase activity inhibit binding a natural effector have also been demonstrated. This review will describe effects of induced proximity, discuss current methods identify molecular introduce approaches could be adapted for glue screening.
Язык: Английский
Процитировано
10
Chemical Biology & Drug Design, Год журнала: 2024, Номер 104(5)
Опубликована: Ноя. 1, 2024
Cereblon (CRBN), a member of the E3 ubiquitin ligase complex, has gained significant attention as therapeutic target in cancer. CRBN regulates degradation various proteins cancer progression, including transcription factors and signaling molecules. PROTACs (proteolysis-targeting chimeras) are novel approach that uses cell's system to remove disease-causing selectively. CRBN-dependent work by tagging harmful for destruction through ubiquitin-proteasome system. This strategy offers several advantages over traditional protein inhibition methods, potential overcome drug resistance. Recent progress developing CRBN-based shown promising preclinical results both hematologic malignancies solid tumors. Additionally, have enhanced our understanding CRBN's role cancer, potentially serving biomarkers patient stratification predicting responses. In this review, we delineate mechanisms action (CRBN-PROTACs), summarize recent advances clinical applications, provide perspective on future development.
Язык: Английский
Процитировано
3
bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown
Опубликована: Янв. 28, 2024
Abstract Targeted protein degradation (TPD) has emerged as a powerful strategy to selectively eliminate cellular proteins using small-molecule degraders, offering therapeutic promise for targeting that are otherwise undruggable. However, remaining challenge is unambiguously identify primary TPD targets distinct from secondary downstream effects in the proteome. Here we introduce an approach combines stable isotope labeling and click-chemistry selective quantification of by mass spectrometry, excluding confounding altered transcription translation induced target depletion. We show efficiently operates at time scale (hours) demonstrate its utility analyzing Cyclin K degraders dCeMM2 dCeMM4, which induce widespread transcriptional downregulation, GSPT1 degrader CC-885, inhibitor translation. Additionally, apply it characterize compound 1, previously uncharacterized degrader, zinc-finger FIZ1 degraded target.
Язык: Английский
Процитировано
2
Medicinal Research Reviews, Год журнала: 2024, Номер 44(4), С. 1727 - 1767
Опубликована: Фев. 5, 2024
Abstract Unprecedented therapeutic targeting of previously undruggable proteins has now been achieved by molecular‐glue‐mediated proximity‐induced degradation. As a small GTPase, G1 to S phase transition 1 (GSPT1) interacts with eRF1, the translation termination factor, facilitate process termination. Studied demonstrated that GSPT1 plays vital role in acute myeloid leukemia (AML) and MYC‐driven lung cancer. Thus, molecular glue (MG) degraders is novel promising approach for treating AML cancers. In this Perspective, we briefly summarize structural functional aspects GSPT1, highlighting latest advances challenges MG degraders, as well some representative patents. The structure‐activity relationships, mechanism action pharmacokinetic features are emphasized provide comprehensive compendium on rational design degraders. We hope an updated overview, guide strategies treatment
Язык: Английский
Процитировано
2