RSC Medicinal Chemistry, Год журнала: 2024, Номер unknown
Опубликована: Дек. 30, 2024
ER PROTACs emerge as a hopeful and innovative strategy for combating endocrine-resistant breast cancer.
Язык: Английский
Expert Opinion on Drug Discovery, Год журнала: 2025, Номер unknown
Опубликована: Фев. 16, 2025
Degraders are an increasingly important sub-modality of small molecules as illustrated by ever-expanding number publications and clinical candidate in human trials. Nevertheless, their preclinical optimization ADME PK/PD properties has remained challenging. Significant research efforts being directed to elucidate underlying principles derive rational strategies. In this review the authors summarize current best practices terms vitro assays vivo experiments. Furthermore, collate comment on understanding optimal physicochemical characteristics impact absorption, distribution, metabolism excretion including knowledge Drug-Drug interactions. Finally, describe Pharmacokinetic prediction Pharmacokinetic/Pharmacodynamic -concepts unique degraders how implement these projects. Despite many recent advances field, continued will further our design regarding degrader optimization. Machine-learning computational approaches become once larger, more robust datasets available. tissue-targeting (particularly Central Nervous System be studied efficacious drug regimens that capitalize catalytic mode action. additional specialized (e.g. covalent degraders, LOVdegs) can enrich field offer interesting alternative approaches.
Язык: Английский
Процитировано
1
ACS Chemical Biology, Год журнала: 2025, Номер unknown
Опубликована: Янв. 30, 2025
Conventional small-molecule drugs primarily operate by inhibiting protein function, but this approach is limited when proteins lack well-defined ligand-binding pockets. Targeted degradation (TPD) offers an alternative harnessing cellular pathways to eliminate specific proteins. Recent studies have expanded the potential of TPD identifying additional E3 ligases, with DCAF16 emerging as a promising candidate for facilitating through both proteolysis-targeting chimera (PROTAC) and molecular glue mechanisms. In study, we revisited previously reported compound discovered that it covalently binds DCAF16. We further optimized into FKBP12-targeting PROTAC, MC-25B. This PROTAC engages at cysteines C177-179, leading nuclear-localized FKBP12. demonstrated versatility recruiter degrading endogenous Compared first-generation DCAF16-based which was derived from fragment electrophile, recruiter-based exhibits improved proteome-wide selectivity.
Язык: Английский
Процитировано
0
European Journal of Medicinal Chemistry, Год журнала: 2025, Номер 289, С. 117432 - 117432
Опубликована: Фев. 20, 2025
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
Accounts of Chemical Research, Год журнала: 2025, Номер unknown
Опубликована: Март 25, 2025
ConspectusTargeted protein degradation (TPD) technologies, exemplified by proteolysis-targeting chimeras (PROTACs), have revolutionized therapeutic strategies facilitating the selective of pathogenic proteins instead simply inhibiting their functions. This degradation-based strategy offers significant advantages over traditional small-molecule inhibitors, which often block activity without eliminating target. PROTACs function leveraging ubiquitin-proteasome system to selectively degrade target proteins, thus enabling modulation a broader range disease-causing including those that were previously considered undruggable. As result, PROTAC-based therapies gained considerable attention in drug discovery, especially oncology, immunology, and neurodegenerative diseases. However, clinical translation conventional remains challenging due issues such as limited specificity, poor solubility, inadequate cellular permeability, unfavorable pharmacokinetic profiles, absence spatiotemporal resolution.To address these hurdles, various innovative been developed enhance precision degradation. These approaches focus on improving targeted delivery, membrane control with goal overcoming inherent limitations PROTAC designs. For instance, aptamer-conjugated shown great promise tumor selectivity reducing off-target effects through tumor-specific receptor recognition subsequent internalization. Moreover, development drugtamer-PROTAC conjugates enables more precise codelivery agents, optimizing synergistic both modalities while minimizing systemic toxicity. Additionally, RGD peptide-based conjugation capitalize use tumor-homing peptides uptake, improve penetration, increase specificity cells, further toxicities healthy tissues.Another critical advancement is photocontrolled PROTACs, allow for temporal regulation vivo. By light-responsive molecules, systems provide ability trigger at specific time points, offering unparalleled interventions. Furthermore, theranostic combine diagnostic functions, facilitate real-time monitoring events living cells animal models, simultaneous assessment efficacy biomarker visualization.This Account reviews recent advancements design smart highlighting control. innovations promising solutions paving way progress discovery evolution medicine. While discussed present opportunities, we also explore challenges, limitations, future directions translation, insights into potential degrader-based setting.
Язык: Английский
Процитировано
0
Future Medicinal Chemistry, Год журнала: 2024, Номер unknown, С. 1 - 3
Опубликована: Окт. 7, 2024
Keywords: : E3 ligasesmolecular gluesPROTACstargeted protein degradationundruggable therapeutic targets
Язык: Английский
Процитировано
0
Digestive Diseases and Sciences, Год журнала: 2024, Номер unknown
Опубликована: Дек. 11, 2024
Язык: Английский
Процитировано
0
RSC Medicinal Chemistry, Год журнала: 2024, Номер unknown
Опубликована: Дек. 30, 2024
ER PROTACs emerge as a hopeful and innovative strategy for combating endocrine-resistant breast cancer.
Язык: Английский
Процитировано
0