PANCS-Inhibitors: A rapid method to directly select for protein-protein interaction inhibitors

Abstract

Aberrant protein-protein interactions (PPIs) drive myriad diseases. Inhibiting these PPIs often relies on discovering molecules that bind to one of the proteins and hoping that this binding inhibits the PPI. Molecular binder discovery often takes months, but a discovery process that ensures that the resulting molecule not only binds a target protein, but selectively inhibits a target PPI, could dramatically accelerate these endeavors. Here, we develop Phage-Assisted Non-Continuous Selection of PPI Inhibitors (PANCS-Inhibitors): a rapid screening platform that directly selects for molecules capable of disrupting a pre-formed PPI. We demonstrate this new platform using three clinically relevant oncogenic PPIs: KRas-Raf, Mdm2-p53, and Myc-Max. PANCS-Inhibitors can be used to both improve known PPI inhibitors and for de novo discovery of mini-protein PPI inhibitors that function in mammalian cells. This platform has the potential to rapidly generate inhibitors for many clinically relevant PPIs, which can be used as starting points for therapeutic development.