Small molecule inhibitors of RAS-effector protein interactions derived using an intracellular antibody fragment.
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Date
2018-08-09ICR Author
Author
Quevedo, CE
Cruz-Migoni, A
Bery, N
Miller, A
Tanaka, T
Petch, D
Bataille, CJR
Lee, LYW
Fallon, PS
Tulmin, H
Ehebauer, MT
Fernandez-Fuentes, N
Russell, AJ
Carr, SB
Phillips, SEV
Rabbitts, TH
Type
Journal Article
Metadata
Show full item recordAbstract
Targeting specific protein-protein interactions (PPIs) is an attractive concept for drug development, but hard to implement since intracellular antibodies do not penetrate cells and most small-molecule drugs are considered unsuitable for PPI inhibition. A potential solution to these problems is to select intracellular antibody fragments to block PPIs, use these antibody fragments for target validation in disease models and finally derive small molecules overlapping the antibody-binding site. Here, we explore this strategy using an anti-mutant RAS antibody fragment as a competitor in a small-molecule library screen for identifying RAS-binding compounds. The initial hits are optimized by structure-based design, resulting in potent RAS-binding compounds that interact with RAS inside the cells, prevent RAS-effector interactions and inhibit endogenous RAS-dependent signalling. Our results may aid RAS-dependent cancer drug development and demonstrate a general concept for developing small compounds to replace intracellular antibody fragments, enabling rational drug development to target validated PPIs.
Collections
Subject
Cell Line, Tumor
Humans
ras Proteins
Immunoglobulin Fragments
Recombinant Proteins
Antibodies
Binding Sites, Antibody
Crystallography, X-Ray
Surface Plasmon Resonance
Signal Transduction
Cell Survival
Protein Binding
Mutation
Small Molecule Libraries
HEK293 Cells
Biomarkers
Protein Domains
Research team
Chromosomal Translocations and Intracellular Antibody Therapeutics
Language
eng
Date accepted
2018-07-18
License start date
2018-08-09
Citation
Nature communications, 2018, 9 (1), pp. 3169 - ?
Publisher
NATURE PORTFOLIO
Except where otherwise noted, this item's license is described
as
https://creativecommons.org/licenses/by/4.0
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