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

  • Bioorg Med Chem Lett. 2023 Aug 15;92:129385. doi: 10.1016/j.bmcl.2023.129385.
Christina N Di Marco  1 ,  Lamont Terrell  2 ,  Robert Sanchez  2 ,  Lourdes Rueda  2 ,  Leanna Shuster  2 ,  Eldridge N Nartey  2 ,  Charles McHugh  3 ,  James F Mack  2 ,  Arthur Shu  2 ,  Xinrong Tian  2 ,  Jesus R Medina  2 ,  Ralph Rivero  2 ,  Roman Manetsch  4 ,  Dirk Heerding  2 ,  Biju Mangatt  2
Affiliations
  • 1. Medicinal Science and Technology, GSK, Collegeville, PA 19426, USA; Department of Chemistry and Chemical Biology, Northeastern University, Boston, MA 02115, USA. Electronic address: [email protected].
  • 2. Medicinal Science and Technology, GSK, Collegeville, PA 19426, USA.
  • 3. Drug Metabolism and Pharmacokinetics, Research In Vivo/In Vitro Translation, GSK, Collegeville, PA 19426, USA.
  • 4. Department of Chemistry and Chemical Biology, Northeastern University, Boston, MA 02115, USA; Department of Pharmaceutical Sciences, Northeastern University, Boston, MA 02115, USA; Center for Drug Discovery, Northeastern University, Boston, MA 02115, USA; Barnett Institute of Chemical and Biological Analysis, Northeastern University, Boston, MA 02115, USA.
PMID: 37339719 DOI: 10.1016/j.bmcl.2023.129385
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.
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