Irreversibly Silencing Oncogenic Master-regulator cMyc Using Library-derived Electrophilic Helical Peptides

Project: Research council

Project Details

Description

A human gene that has been found to be crucial in the development of over 70% of all cancers is known as MYC. This gene codes for a protein (called cMyc) that is responsible for transforming normal cells to cancer cells and promoting cancer cell growth and tumour formation.

cMyc is a difficult protein to target with antibody-based drugs because it exists inside the nucleus of cancer cells where antibodies cannot go. cMyc is also a difficult protein to target with small molecule drugs that can enter the nucleus of cancer cells but cannot readily block the interactions cMyc makes across large surface areas with other proteins and DNA. No small molecules are known to block cMyc-protein interactions, and only a few small molecules of very low potency block Myc-DNA interactions.

Here we will develop and test a new approach to generating therapeutics that can, in the long term, overcome these problems by silencing cMyc and kill Myc-expressing cancer cells without killing normal human cells.

We propose to screen libraries of amino acid-containing peptides inside cells to find those with the best ability to selectively bind to cMyc. We have developed a method for tightening the binding of peptides to the target protein through adding a chemical 'electrophile' that sticks the peptide to the protein like a safety pin mechanism. Optimised peptides will bind selectively to cMyc and not come off. This approach can chemically silence cMyc and prevent it from promoting cancer. Our preliminary data demonstrates that this approach can work in that we have found that we can irreversibly bind peptides to cMyc and stop its binding to protein partners present inside cells, potentially silencing its functions and causing cancer cell death without killing normal cells.

The proposal seeks to build upon our strong proof-of-concept pilot data to optimise the peptide sequences for:

(a) selective binding to the protein cMyc,
(b) tight and irreversible binding to the protein cMyc,
(c) maximum uptake of the peptides into cancer cells and further into their nucleus,
(d) irreversible binding to cMyc inside the nucleus of cancer cells,
(e) inducing death of a range of cMyc-expressing human cancer cells without killing normal cells.

Success in these endeavours will be of exceptional interest to pharmaceutical companies and medical researchers who are becoming excited about cMyc as a new target for cancer. We present an entirely new and viable therapeutic approach to a very promising new cancer target. The technology developed will be potentially transferable to other protein-protein interactions (PPIs) implicated in disease pathways.
StatusActive
Effective start/end date1/12/2030/11/23

Funding

  • Medical Research Council