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

Christina N Di Marco; Lamont Terrell; Robert Sanchez; Lourdes Rueda; Leanna Shuster; Eldridge N Nartey; Charles McHugh; James F Mack; Arthur Shu; Xinrong Tian; Jesus R Medina; Ralph Rivero; Roman Manetsch; Dirk Heerding; Biju Mangatt

doi:10.1016/j.bmcl.2023.129385

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. Epub 2023 Jun 18.

Authors

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.

MeSH terms

Aminopyridines*
Animals
Benzimidazoles
Gene Expression Regulation
Proto-Oncogene Proteins c-myc* / metabolism
Rats
Transcription Factors / metabolism

Substances

Aminopyridines
Proto-Oncogene Proteins c-myc
Transcription Factors
Benzimidazoles