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, Terence H. Rabbitts

Allbwn ymchwil: Cyfraniad at gyfnodolynErthygladolygiad gan gymheiriaid

99 Dyfyniadau (Scopus)
254 Wedi eu Llwytho i Lawr (Pure)

Crynodeb

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.
Iaith wreiddiolSaesneg
Rhif yr erthygl3169
CyfnodolynNature Communications
Cyfrol9
Rhif cyhoeddi1
Dyddiad ar-lein cynnar09 Awst 2018
Dynodwyr Gwrthrych Digidol (DOIs)
StatwsCyhoeddwyd - 01 Rhag 2018

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