Conformational drugging pockets at the surface of c-MYC proto-oncongenes

Abstract

The MYC proto-oncogene encodes a master transcription factor essential for regulating cellular homeostasis, growth, and metabolism. However, its deregulation is involved in up to 70% of human cancers, where it drives uncontrolled cellular proliferation. Structurally, MYC is characterized by an N-terminal transactivation domain and a C-terminal bHLHLZ domain critical for DNA binding and dimerization with MAX. Despite its clinical significance, MYC has remained historically "undruggable" due to its intrinsically disordered structure and the absence of traditional binding pockets. In this study, we combined all-atom Molecular Dynamics and well-tempered Metadynamics simulations to map the conformational landscape of a MYC motif in aqueous ionic solution. The selected energy-minimised structures exhibit stable conformations and drug pockets, providing structural foundations for targetting c-MYC, which is traditionally considered "undruggable". Furthermore, both the electrostatic potential and docking results for the obtained structure and the MYC inhibitor 10074-G5 demonstrated excellent fit, highlighting its potential as a drug target. Remarkably, MYC maintained steady binding to 10074-G5 throughout the 500 ns simulation. These findings provide a previously uncharacterized structural foundation for the design of innovative therapeutic interventions, such as small-molecule inhibitors or peptides aimed at disrupting oncogenic MYC activity.