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Small molecule inhibitors of RAS-effector protein interactions derived using an intracellular antibody fragment

DOI: 10.1038/s41467-018-05707-2 DOI Help

Authors: Camilo E. Quevedo (University of Oxford) , Abimael Cruz-migoni (Weatherall Institute of Molecular Medicine, University of Oxford; Research Complex at Harwell) , Nicolas Bery (Weatherall Institute of Molecular Medicine, University of Oxford) , Ami Miller (Weatherall Institute of Molecular Medicine, University of Oxford) , Tomoyuki Tanaka (Leeds Institute for Molecular Medicine, St James University Hospital) , Donna Petch (Leeds Institute for Molecular Medicine, St James University Hospital) , Carole J. R. Bataille (Chemistry Research Laboratory) , Lydia Y. W. Lee (Domainex) , Phillip S. Fallon (Domainex) , Hanna Tulmin (University of Oxford) , Matthias T. Ehebauer (Weatherall Institute of Molecular Medicine, University of Oxford) , Narcis Fernandez-fuentes (Research Complex at Harwell; University of Aberystwyth) , Angela J. Russell (Chemistry Research Laboratory) , Stephen Carr (Research Complex at Harwell; University of Oxford) , Simon E. V. Phillips (Research Complex at Harwell; University of Oxford) , Terence Rabbitts (Weatherall Institute of Molecular Medicine, University of Oxford)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Nature Communications , VOL 9

State: Published (Approved)
Published: August 2018
Diamond Proposal Number(s): 9306 , 13456

Open Access Open Access

Abstract: 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.

Journal Keywords: Oncogene proteins; Screening; Structure-based drug design; X-ray crystallography

Subject Areas: Biology and Bio-materials, Medicine


Instruments: I02-Macromolecular Crystallography , I03-Macromolecular Crystallography , I04-1-Macromolecular Crystallography (fixed wavelength)

Other Facilities: European Synchrotron Radiation Facility

Documents:
s41467-018-05707-2.pdf