High-throughput screening for compounds to enhance expression from the low density lipoprotin receptor using a novel genomic DNA based luciferase assay

We screened and identified a series of small molecules from a genomic DNA reporter screen that upregulate the LDLR in mouse and human liver cell lines at nanomolar potencies (EC50 5 39 nM). Structure-activity relationship studies carried out on the lead compound, OX03771 [(E)-N,N-dimethyl-3-(4-styrylphenoxy)propan-1-amine], led to the identification of compound OX03050 [(E)-3-(4-styrylphenoxy)propan-1-ol],which had similar potency (EC50526 nM) but a much-improved pharmacokinetic profile and showed in vivo efficacy. Compounds OX03050 and OX03771 were found to inhibit squalene synthase, the first committed step in cholesterol biosynthesis. These squalene synthase inhibitors were shown to act cooperatively with statins to increase LDLR expression in vitro.

Overall, we defined a novel series of small molecules with the potential to be further developed to treat patients either alone or in combination with statins.

Publication linked to this award:

1. Kerr AG, Tam LCS, Hale AB, Cioroch M, Douglas G, Agkatsev S, Hibbitt O, Mason J, Holt-Martyn J, Bataille CJR, Wynne GM, Channon KM, Russell AJ, Wade-Martins R. (2017) A Genomic DNA Reporter Screen Identifies Squalene Synthase Inhibitors That Act Cooperatively with Statins to Upregulate the Low-Density Lipoprotein Receptor. J Pharmacol Exp Ther. 2017 Jun;361(3):417-428. PMID: 28360334