Design and synthesis of aminopyridine containing biaryls reducing c-MYC protein levels in cells

Area of Science:

• Medicinal Chemistry
• Oncology
• Molecular Biology

Background:

• The c-MYC oncogene plays a crucial role in cell cycle regulation, controlling cell growth and proliferation.
• Dysregulation of c-MYC is common in various cancers, making it a significant therapeutic target.
• Previous Structure-Activity Relationship (SAR) studies explored benzimidazole cores for c-MYC inhibition.

Purpose of the Study:

• To identify novel scaffolds with improved properties for c-MYC inhibition.
• To evaluate benzimidazole core replacements for enhanced therapeutic potential.
• To advance lead optimization for c-MYC-targeted cancer therapies.

Main Methods:

• Synthesis and evaluation of a series of analogues with benzimidazole core replacements.
• Assessment of c-MYC HTRF pEC50 values to determine inhibitory potency.
• Evaluation of lipophilicity, solubility, and rat pharmacokinetics for drug-likeness.

Main Results:

• Identification of imidazopyridazine compounds with equivalent or superior c-MYC HTRF pEC50 values compared to benzimidazole analogues.
• Imidazopyridazine compounds demonstrated favorable lipophilicity, solubility, and pharmacokinetic profiles in rats.
• The imidazopyridazine core emerged as a superior scaffold for further medicinal chemistry efforts.

Conclusions:

• The imidazopyridazine core represents a viable and advantageous alternative to the benzimidazole core for developing c-MYC-targeting agents.
• These findings support continued lead optimization and medicinal chemistry campaigns focused on the imidazopyridazine scaffold.
• This research contributes to the development of novel oncogenic therapies targeting the deregulated c-MYC pathway in cancer.