PockEdit – Large scale mapping of druggable pockets in the human proteome to identify novel therapeutic targets for cancer treatment.

Targeted cancer therapies rely on the development of drugs that bind to specific protein pockets required for cancer cell survival.

While we know all the druggable pockets in the human proteome, we lack methods to determine which of them might be used to kill cancer cells. Such a method would transform cancer research and accelerate the development of cancer therapies.

We propose to develop a novel approach called PockEdit that uses a unique, large-scale lentiviral base-editing screen to mutate ~90000 residues in ~18000 druggable pockets of the human proteome.

Combined with competitive growth assays and next generation sequencing, this will allow us to accurately map druggable pockets in any given cancer cell line. The library will include active sites of enzymes, interfaces of protein-protein interactions, and allosteric sites.

We will use PockEdit in different cancer cell lines and genetic contexts and in combination with anticancer drugs to discover and validate novel drug pockets.

The outcome of this proposal will be a general method to map druggable pockets for different cancer cells and provide researchers with new targets for cancer therapy development.

A future perspective would be to screen all available cancer cell lines with PockEdit to provide the research community with precise information on how to target specific cancer types.