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

Camilo E. Quevedo, Abimael Cruz-Migoni, Nicolas Bery, Ami Miller, Tomoyuki Tanaka, Donna Petch, Carole J. R. Bataille, Lydia Y. W. Lee, Phillip S. Fallon, Hanna Tulmin, Matthias T. Ehebauer, Narcis Fernandez-Fuentes, Angela J. Russell, Stephen B. Carr, Simon E. V. Phillips and Terence H. Rabbitts ()
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Camilo E. Quevedo: University of Oxford, John Radcliffe Hospital
Abimael Cruz-Migoni: University of Oxford, John Radcliffe Hospital
Nicolas Bery: University of Oxford, John Radcliffe Hospital
Ami Miller: University of Oxford, John Radcliffe Hospital
Tomoyuki Tanaka: St James University Hospital
Donna Petch: St James University Hospital
Carole J. R. Bataille: Chemistry Research Laboratory
Lydia Y. W. Lee: Little Chesterford
Phillip S. Fallon: Little Chesterford
Hanna Tulmin: University of Oxford, John Radcliffe Hospital
Matthias T. Ehebauer: University of Oxford, John Radcliffe Hospital
Narcis Fernandez-Fuentes: Rutherford Appleton Laboratory
Angela J. Russell: Chemistry Research Laboratory
Stephen B. Carr: Rutherford Appleton Laboratory
Simon E. V. Phillips: Rutherford Appleton Laboratory
Terence H. Rabbitts: University of Oxford, John Radcliffe Hospital

Nature Communications, 2018, vol. 9, issue 1, 1-12

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-05707-2

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