Development of PROTACs targeting estrogen receptor: An emerging technique for combating endocrine resistance DOI
Rouming Peng, Xin Liu, Chun‐Chi Chen

et al.

RSC Medicinal Chemistry, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 30, 2024

ER PROTACs emerge as a hopeful and innovative strategy for combating endocrine-resistant breast cancer.

Language: Английский

Finding a needle in the haystack: ADME and pharmacokinetics/pharmacodynamics characterization and optimization toward orally available bifunctional protein degraders DOI
Giulia Apprato, Giulia Caron, Gauri Deshmukh

et al.

Expert Opinion on Drug Discovery, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 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.

Language: Английский

Citations

1
Discovery of DCAF16 Binders for Targeted Protein Degradation DOI
Miguel Campos,

Isabella A. Riha,

Chenlu Zhang

et al.

ACS Chemical Biology, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 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.

Language: Английский

Citations

0
In silico modeling of targeted protein degradation DOI Creative Commons
Wenxing Lv,

Xiaojuan Jia,

Bowen Tang

et al.

European Journal of Medicinal Chemistry, Journal Year: 2025, Volume and Issue: 289, P. 117432 - 117432

Published: Feb. 20, 2025

Language: Английский

Citations

0
Application of Mass Spectrometry for the Advancement of PROTACs DOI
Hao Yin,

Baoshuang Zhang,

Ruibing Chen

et al.

Journal of Pharmaceutical and Biomedical Analysis, Journal Year: 2025, Volume and Issue: unknown, P. 116829 - 116829

Published: March 1, 2025

Language: Английский

Citations

0
Strategies for Precise Modulation of Protein Degradation DOI
Shipeng He, Guoqiang Dong, Chunquan Sheng

et al.

Accounts of Chemical Research, Journal Year: 2025, Volume and Issue: unknown

Published: March 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.

Language: Английский

Citations

0
A long march for targeted protein degradation in the new era: expanding E3 ligases DOI Creative Commons
Dazhao Mi,

A.D. Huang,

Song Jingfeng

et al.

Future Medicinal Chemistry, Journal Year: 2024, Volume and Issue: unknown, P. 1 - 3

Published: Oct. 7, 2024

Keywords: : E3 ligasesmolecular gluesPROTACstargeted protein degradationundruggable therapeutic targets

Language: Английский

Citations

0
E3 Ubiquitination Ligase MYLIP Mediates the NKRF/SLC25A34 Axis to Suppress Malignant Progression in Colorectal Cancer DOI
Chao Li, Gang Yu, Wanjing Chen

et al.

Digestive Diseases and Sciences, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 11, 2024

Language: Английский

Citations

0
Development of PROTACs targeting estrogen receptor: An emerging technique for combating endocrine resistance DOI
Rouming Peng, Xin Liu, Chun‐Chi Chen

et al.

RSC Medicinal Chemistry, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 30, 2024

ER PROTACs emerge as a hopeful and innovative strategy for combating endocrine-resistant breast cancer.

Language: Английский

Citations

0