Breaking the 'undruggable' barrier: Revealing molecular mechanisms in Aurora Kinase A/Myc protein interplay targeting cancers

Abstract

The intricate interplay between Aurora Kinase A (AURKA) and the elusive oncogene N-myc plays a pivotal role in the progression of numerous cancers. Disrupting N-myc destabilization through targeted inhibition of Aurora Kinase A's ATP binding site has emerged as a promising strategy to impede cancer progression. Notably, inhibitors like Fostamatinib and Alisertib have demonstrated the complete disruption of the Aurora Kinase A and N-myc interface, crucial for preventing dysregulation of the cell cycle and uncontrolled cell proliferation. Despite successes, challenges persist, including drug resistance and toxicity concerns, particularly with Alisertib observed in Phase 3 clinical trials. This underscores the imperative for novel inhibitors with enhanced efficacy and reduced adverse effects. The hypothesis suggests that strategic targeting of Aurora-A's ATP-binding site can interfere with the detailed interaction between Aurora-A and N-Myc, potentially leading to N-Myc degradation. This approach overcomes the limitation of MYC being an undruggable target. To address this, we propose leveraging computational predictions and experimental validations, including molecular dynamics simulations, to delineate the molecular interface, predict compounds, and elucidate interactions with Aurora-A. These simulations offer insights into the dynamic nature of the AurKA/N-myc complex in the presence of inhibitors, providing a basis for designing novel compounds targeting specific regions. Interface dynamic studies of the AurKA/N-myc axis aim to uncover non-toxic, biocompatible, and selective inhibitors. Experimental assays will validate inhibitory effects, offering insights into the compounds' effectiveness. This hypothesis could pave the way for innovative, effective, and safer therapeutic agents in cancer treatment.