Structure-based discovery of hydrocarbon-stapled paxillin peptides that block FAK scaffolding in cancer

Lauren Reyes, Lena Naser, Warren S. Weiner, Darren Thifault, Erik Stahl, Liam McCreary, Rohini Nott, Colton Quick, Alex Buchberger, Carlos Alvarado, Andrew Rivera, Joseph A. Miller, Ruchi Khatiwala, Brian R. Cherry, Ronald Nelson, Jose M. Martin-Garcia, Nicholas Stephanopoulos, Raimund Fromme, Petra Fromme, William Cance and Timothy Marlowe ()
Additional contact information
Lauren Reyes: University of Arizona College of Medicine – Phoenix
Lena Naser: University of Arizona College of Medicine – Phoenix
Warren S. Weiner: University of Arizona College of Medicine – Phoenix
Darren Thifault: Arizona State University
Erik Stahl: University of Arizona College of Medicine – Phoenix
Liam McCreary: University of Arizona College of Medicine – Phoenix
Rohini Nott: University of Arizona College of Medicine – Phoenix
Colton Quick: LLC
Alex Buchberger: Arizona State University
Carlos Alvarado: University of Arizona College of Medicine – Phoenix
Andrew Rivera: University of Arizona College of Medicine – Phoenix
Joseph A. Miller: University of Arizona College of Medicine – Phoenix
Ruchi Khatiwala: University of Arizona College of Medicine – Phoenix
Brian R. Cherry: Arizona State University
Ronald Nelson: University of Arizona College of Medicine – Phoenix
Jose M. Martin-Garcia: Institute of Physical Chemistry Blas Cabrera
Nicholas Stephanopoulos: Arizona State University
Raimund Fromme: Arizona State University
Petra Fromme: Arizona State University
William Cance: University of Arizona College of Medicine – Phoenix
Timothy Marlowe: University of Arizona College of Medicine – Phoenix

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: Abstract The focal adhesion kinase (FAK) scaffold provides FAK-targeted cancer therapeutics with greater efficacy and specificity than traditional kinase inhibitors. The FAK scaffold function largely involves the interaction between FAK’s focal adhesion targeting (FAT) domain and paxillin, ultimately regulating many hallmarks of cancer. We report the design of paxillin LD-motif mimetics that successfully inhibit the FAT-paxillin interaction. Chemical and biochemical screening identifies stapled peptide 1907, a high affinity binder of the FAT four-helix bundle with ~100-fold greater binding affinity than the native LD2-sequence. The X-ray co-crystal structure of the FAT-1907 complex is solved. Myristoylated 1907-analog, peptide 2012, delocalizes FAK from focal adhesions, induces cancer cell apoptosis, reduces in vitro viability and invasion, and decreases tumor burden in B16F10 melanoma female mice. Enzymatic FAK inhibition produces no comparable effects. Herein, we describe a biologically potent therapeutic strategy to target the FAK-paxillin complex, a previously deemed undruggable protein-protein interaction.

Date: 2025
References: View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-025-57196-9 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-57196-9

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-025-57196-9

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().