Bifunctional Small‐Molecule Ligands of K‐Ras Induce Its Association with Immunophilin Proteins

Zhang, Ziyang; Shokat, Kevan M.

doi:10.1002/anie.201910124

Cited by 66Protein Kinase Regulation and GTPase SignalingSignaling Pathways in DiseaseChemical Synthesis and Analysis

Bifunctional Small‐Molecule Ligands of K‐Ras Induce Its Association with Immunophilin Proteins

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Zhang, Ziyang, Shokat, Kevan M.·2019·Angewandte Chemie International Edition

DOI 10.1002/anie.201910124PMC PMC6980260

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Abstract

Here we report the design, synthesis, and characterization of bifunctional chemical ligands that induce the association of Ras with ubiquitously expressed immunophilin proteins such as FKBP12 and cyclophilin A. We show this approach is applicable to two distinct Ras ligand scaffolds, and that both the identity of the immunophilin ligand and the linker chemistry affect compound efficacy in biochemical and cellular contexts. These ligands bind to Ras in an immunophilin‐dependent fashion and mediate the formation of tripartite complexes of Ras, immunophilin, and the ligand. The recruitment of cyclophilin A to GTP‐bound Ras blocks its interaction with B‐Raf in biochemical assays. Our study demonstrates the feasibility of ligand‐induced association of Ras with intracellular proteins and suggests it as a promising therapeutic strategy for Ras‐driven cancers.

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The Results and Discussion (page unavailable) describe ARS1620-related KRAS G12C ligands and their cellular target engagement, not a BiTE or a cytotoxic T-cell response. Searches for BiTEs, antigen presentation, and cells resistant to KRAS G12C inhibition found no passage addressing the claimed effect. (LLM, conf=0.76)
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Because cyclophilin A is expressed ubiquitously, diverse RAS-mutant tumour types could be amenable to tri-complex agents.
“Importantly, cyclophilin A is expressed ubiquitously186, and thus diverse RAS-mutant tumour types could be amenable to these agents.”
From The current state of the art and future trends in RAS-targeted cancer therapies (2022) · cites this paper as [186]

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Authors: Zhang, Z., & Shokat, K. M.
Affiliations: Howard Hughes Medical Institute (US)
Corresponding author: Shokat, Kevan M.
ORCID: Zhang, Ziyang
Shokat, Kevan M.
Venue: Angewandte Chemie International Edition
Publisher: Wiley
Published: 2019-09-26
Volume: 58
Issue: 45
Pages: 16314-16319
ISSN: 1433-7851 (ISSN-L)
1521-3773
DOI: 10.1002/anie.201910124
PMC: PMC6980260
OpenAlex: W2976509544
Cited by: 66
References: 41
Citations by year: 2026: 6 · 2025: 12 · 2024: 10 · 2023: 14 · 2022: 5 · 2021: 8 · 2020: 8 · 2019: 3
FWCI: 1.99
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations: Angewandte Chemie International Edition (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
Funders: Damon Runyon Cancer Research Foundation (DRG-2281-17)
Howard Hughes Medical Institute
National Institutes of Health (R01 CA 190408)
Samuel Waxman Cancer Research Foundation
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Signaling Pathways in Disease
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chemical Synthesis and Analysis
Keywords: KRAS, bifunctional ligands, immunophilins, FKBP12, cyclophilin A, linker chemistry, RAS-driven cancers
MeSH terms: Guanosine Triphosphate, Humans, Ligands, Protein Conformation, Proto-Oncogene Proteins p21(ras), Crystallography, X-Ray, Catalytic Domain, Cyclophilins, Tacrolimus Binding Protein 1A, Proto-Oncogene Proteins B-raf, Small Molecule Libraries

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Bifunctional Small‐Molecule Ligands of K‐Ras Induce Its Association with Immunophilin Proteins

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