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

Abstract

The c-MYC oncogene transcription factor has been implicated in cell cycle regulation controlling cell growth and proliferation. It is tightly regulated in normal cells, but has been shown to be deregulated in cancer cells, and is thus an attractive target for oncogenic therapies. Building upon previous SAR, a series of analogues containing benzimidazole core replacements were prepared and evaluated, leading to the identification of imidazopyridazine compounds that were shown to possess equivalent or improved c-MYC HTRF pEC₅₀ values, lipophilicity, solubility, and rat pharmacokinetics. The imidazopyridazine core was therefore determined to be superior to the original benzimidazole core and a viable alternate for continued lead optimization and medicinal chemistry campaigns.

Keywords: Benzimidazole; Biaryl; Imidazopyridazine; Oncogene; Structure–activity relationship (SAR); c-MYC.