A moving target: structure and disorder in pursuit of Myc inhibitors

Area of Science:

• Molecular Biology
• Structural Biology
• Cancer Research

Background:

• Myc proteins are crucial gene regulators involved in over 50% of human cancers.
• Their intrinsically disordered nature complicates structural characterization of protein interactions.
• Understanding Myc-protein interactions is key to developing targeted cancer therapies.

Purpose of the Study:

• To determine the structural basis of the interaction between N-Myc and Aurora-A kinase.
• To elucidate the mechanism by which kinase inhibitors disrupt this protein-protein interaction.
• To inform the development of novel protein-protein interaction inhibitors for cancer treatment.

Main Methods:

• Determined the crystal structure of the Aurora-A kinase domain bound to an N-Myc fragment.
• Analyzed the structural features of the N-Myc transactivation domain and its binding site on Aurora-A.
• Investigated the effect of ATP-competitive inhibitors on the Myc-Aurora-A interaction.

Main Results:

• Revealed an α-helical segment in N-Myc, stabilized by tryptophan residues, binding to Aurora-A.
• Demonstrated that Aurora-A acts as a scaffold, ordering the N-Myc region independently of its catalytic activity.
• Showed that inhibitors like MLN8237 (alisertib) and CD532 disrupt the N-Myc binding site, leading to Myc destabilization.

Conclusions:

• The determined structure provides a molecular basis for Myc-Aurora-A interaction and its disruption by kinase inhibitors.
• This structural insight is crucial for designing protein-protein interaction inhibitors targeting Myc pathways.
• Developing Myc inhibitors holds promise for novel cancer therapeutic strategies.