1. Nilotinib: Disrupting the MYC-MAX Heterocomplex
- Author
-
Kamilla Shah MS, Maham Ansari MS, Samina Saeed MS, Abdul Wali PhD, and Muhammad Mushtaq Yasinzai PhD
- Subjects
Biology (General) ,QH301-705.5 - Abstract
MYC is a transcription factor crucial for maintaining cellular homeostasis, and its dysregulation is associated with highly aggressive cancers. Despite being considered “undruggable” due to its unstable protein structure, MYC gains stability through its interaction with its partner protein, MAX. The MYC-MAX heterodimer orchestrates the expression of numerous genes that contribute to an oncogenic phenotype. Previous efforts to develop small molecules, disrupting the MYC-MAX interaction, have shown promise in vitro but none have gained clinical approval. Our current computer-aided study utilizes an approach to explore drug repurposing as a strategy for inhibiting the c-MYC-MAX interaction. We have focused on compounds from DrugBank library, including Food and Drug Administration-approved drugs or those under investigation for other medical conditions. First, we identified a potential druggable site on flat interface of the c-MYC protein, which served as the target for virtual screening. Using both activity-based and structure-based screening, we comprehensively assessed the entire DrugBank library. Structure-based virtual screening was performed on AutoDock Vina and Glide docking tools, while activity-based screening was performed on two independent quantitative structure-activity relationship models. We focused on the top 2% of hit molecules from all screening methods. Ultimately, we selected consensus molecules from these screenings—those that exhibited both a stable interaction with c-MYC and superior inhibitory activity against c-MYC-MAX interaction. Among the evaluated molecules, we identified a protein kinase inhibitor (tyrosine kinase inhibitor [TKI]) known as nilotinib as a promising candidate targeting c-MYC-MAX dimer. Molecular dynamic simulations demonstrated a stable interaction between MYC and nilotinib. The interaction with nilotinib led to the stabilization of a region of the MYC protein that is distorted in apo-MYC and is important for MAX binding. Further analysis of differentially expressed gene revealed that nilotinib, uniquely among the tested TKIs, induced a gene expression program in which half of the genes were known to be responsive to c-MYC. Our findings provide the foundation for subsequent in vitro and in vivo investigations aimed at evaluating the efficacy of nilotinib in managing MYC oncogenic activity.
- Published
- 2024
- Full Text
- View/download PDF