Harnessing the FBXW7 Somatic Mutant R465C for Targeted Protein Degradation

Ananya A. Basu; Chenlu Zhang; Milad Rouhimoghadam; Anil Vasudevan; Justin M. Reitsma; Xiaoyu Zhang

doi:10.1021/jacs.4c17331

Harnessing the FBXW7 Somatic Mutant R465C for Targeted Protein Degradation

Ananya A. Basu, Chenlu Zhang, Milad Rouhimoghadam, Anil Vasudevan, Justin M. Reitsma, Xiaoyu Zhang^*

^*Corresponding author for this work

Chemistry

Research output: Contribution to journal › Article › peer-review

Abstract

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

Original language	English (US)
Pages (from-to)	6108-6115
Number of pages	8
Journal	Journal of the American Chemical Society
Volume	147
Issue number	7
DOIs	https://doi.org/10.1021/jacs.4c17331
State	Published - Feb 19 2025

Funding

We gratefully acknowledge the support of the NIH R00 CA248715 (X.Z.), NIH T32 GM105538 (A.A.B.), Damon Runyon Cancer Research Foundation DFS-53-22 (X.Z.), and the Chemistry of Life Processes Institute Cornew Innovation Award (X.Z.).

ASJC Scopus subject areas

Catalysis
General Chemistry
Biochemistry
Colloid and Surface Chemistry

Access to Document

10.1021/jacs.4c17331

Cite this

@article{64cb74008617471194241b82f391184d,

title = "Harnessing the FBXW7 Somatic Mutant R465C for Targeted Protein Degradation",

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

author = "Basu, {Ananya A.} and Chenlu Zhang and Milad Rouhimoghadam and Anil Vasudevan and Reitsma, {Justin M.} and Xiaoyu Zhang",

note = "Publisher Copyright: {\textcopyright} 2025 American Chemical Society.",

year = "2025",

month = feb,

day = "19",

doi = "10.1021/jacs.4c17331",

language = "English (US)",

volume = "147",

pages = "6108--6115",

journal = "Journal of the American Chemical Society",

issn = "0002-7863",

publisher = "American Chemical Society",

number = "7",

}

TY - JOUR

T1 - Harnessing the FBXW7 Somatic Mutant R465C for Targeted Protein Degradation

AU - Basu, Ananya A.

AU - Zhang, Chenlu

AU - Rouhimoghadam, Milad

AU - Vasudevan, Anil

AU - Reitsma, Justin M.

AU - Zhang, Xiaoyu

PY - 2025/2/19

Y1 - 2025/2/19

N2 - Targeted protein degradation (TPD) is a pharmacological strategy that eliminates specific proteins from cells by harnessing cellular proteolytic degradation machinery. In proteasome-dependent TPD, expanding the repertoire of E3 ligases compatible with this approach could enhance the applicability of this strategy across various biological contexts. In this study, we discovered that a somatic mutant of FBXW7, R465C, can be exploited by heterobifunctional compounds for targeted protein degradation. This work demonstrates the potential of utilizing mutant E3 ligases that occur exclusively in diseased cells for TPD applications.

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

UR - http://www.scopus.com/inward/record.url?scp=85217031498&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85217031498&partnerID=8YFLogxK

U2 - 10.1021/jacs.4c17331

DO - 10.1021/jacs.4c17331

M3 - Article

C2 - 39913332

AN - SCOPUS:85217031498

SN - 0002-7863

VL - 147

SP - 6108

EP - 6115

JO - Journal of the American Chemical Society

JF - Journal of the American Chemical Society

IS - 7

ER -

Harnessing the FBXW7 Somatic Mutant R465C for Targeted Protein Degradation

Abstract

Funding

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this