Harnessing the FBXW7 somatic mutant R465C for targeted protein degradation DOI Creative Commons
Ananya A. Basu, Chenlu Zhang,

Milad Rouhimoghadam

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 4, 2024

Targeted protein degradation (TPD) is a pharmacological strategy that eliminates specific proteins from cells by harnessing cellular proteolytic machinery. In proteasome-dependent TPD, expanding the repertoire of E3 ligases compatible with this approach could enhance applicability across various biological contexts. study, we discovered somatic mutant FBXW7, R465C, can be exploited heterobifunctional compounds for targeted degradation. This work demonstrates potential utilizing occur exclusively in diseased TPD applications.

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
Harnessing the FBXW7 Somatic Mutant R465C for Targeted Protein Degradation DOI
Ananya A. Basu, Chenlu Zhang,

Milad Rouhimoghadam

et al.

Journal of the American Chemical Society, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 6, 2025

Targeted protein degradation (TPD) is a pharmacological strategy that eliminates specific proteins from cells by harnessing cellular proteolytic machinery. In proteasome-dependent TPD, expanding the repertoire of E3 ligases compatible with this approach could enhance applicability across various biological contexts. study, we discovered somatic mutant FBXW7, R465C, can be exploited heterobifunctional compounds for targeted degradation. This work demonstrates potential utilizing occur exclusively in diseased TPD applications.

Language: Английский

Citations

0
A paradigm shift: analytical ultracentrifugation as a multi-attribute platform method in targeted protein degradation DOI
Alexander E. Yarawsky,

J.A. Ronau,

Tiffany A. Thibaudeau

et al.

European Biophysics Journal, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 17, 2025

Language: Английский

Citations

0
Development of time-resolved luminescence measurement instruments for biosensing and bioimaging – An overview DOI
Benjamin Sreenan, Vala Kafil,

Donovan Wells

et al.

Measurement, Journal Year: 2025, Volume and Issue: unknown, P. 117201 - 117201

Published: March 1, 2025

Language: Английский

Citations

0
Covalent Proximity Inducers DOI Creative Commons
Nir London

Chemical Reviews, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 18, 2024

Molecules that are able to induce proximity between two proteins finding ever increasing applications in chemical biology and drug discovery. The ability introduce an electrophile make such inducers covalent can offer improved properties as selectivity, potency, duration of action, reduced molecular size. This concept has been heavily explored the context targeted degradation particular for bivalent molecules, but recently, additional reported other contexts, well monovalent glues. is a comprehensive review inducers, aiming identify common trends current gaps their discovery application.

Language: Английский

Citations

2
Covalency in PROTACs: Mechanisms and applications DOI
Thomas Geiger, Radosław P. Nowak

Annual reports in medicinal chemistry, Journal Year: 2024, Volume and Issue: unknown, P. 39 - 61

Published: Jan. 1, 2024

Language: Английский

Citations

0
Harnessing the FBXW7 somatic mutant R465C for targeted protein degradation DOI Creative Commons
Ananya A. Basu, Chenlu Zhang,

Milad Rouhimoghadam

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 4, 2024

Targeted protein degradation (TPD) is a pharmacological strategy that eliminates specific proteins from cells by harnessing cellular proteolytic machinery. In proteasome-dependent TPD, expanding the repertoire of E3 ligases compatible with this approach could enhance applicability across various biological contexts. study, we discovered somatic mutant FBXW7, R465C, can be exploited heterobifunctional compounds for targeted degradation. This work demonstrates potential utilizing occur exclusively in diseased TPD applications.

Language: Английский

Citations

0