A Genomic DNA Reporter Screen Identifies Squalene Synthase Inhibitors That Act Cooperatively with Statins to Upregulate the Low-Density Lipoprotein Receptor

Abstract

Hypercholesterolemia remains one of the leading risk factors for the development of cardiovascular disease. Many large double-blind studies have demonstrated that lowering low-density lipoprotein (LDL) cholesterol using a statin can reduce the risk of having a cardiovascular event by approximately 30%. However, despite the success of statins, some patient populations are unable to lower their LDL cholesterol to meet the targeted lipid levels, due to compliance or potency issues. This is especially true for patients with heterozygous familial hypercholesterolemia who may require additional upregulation of the low-density lipoprotein receptor (LDLR) to reduce LDL cholesterol levels below those achievable with maximal dosing of statins. Here we identify 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 = 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 (EC50 = 26 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 demonstrated here a novel series of small molecules with the potential to be further developed to treat patients either alone or in combination with statins.

From 2-Triethylammonium Ethyl Ether of 4-Stilbenol (MG624) to Selective Small-Molecule Antagonists of Human α9α10 Nicotinic Receptor by Modifications at the Ammonium Ethyl Residue

“…The organic layer was dried over anhydrous Na 2 SO 4 , filtered and evaporated under vacuum, providing the desired compound 31 as a white solid in 92% yield. mp = 103-105 °C (coherent with literature 26 ). R f (cyclohexane/EtOAc 1:1 + 3% TEA) = 0.2.…”

“…As in our previous investigation on onium-alkyloxy-stilbene based compounds, the pharmacological characterization of this new series of stilbenol ammoniumalkyl ethers, formally derived from the lead 1 by modification of the cationic head (4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17) or rigidification of the O-N linker (18)(19)(20)(21)(22)(23)(24)(25)(26)(27), started from the evaluation of the α7-nAChR binding affinity by α-Bgtx displacement. This is indicative of competition for the same ACh orthosteric binding sites of this receptor and, in the development of our investigation, a useful guiding criterion in selecting candidates for functional study at both α7and α9α10-nAChR.…”

A factorial Mendelian randomization study to systematically prioritize genetic targets for the treatment of cardiovascular disease

“…This includes FDFT1 which encodes squalene synthase (SQS), a protein downstream HMGCR on the cholesterol biosynthesis pathway 30 . The therapeutic potential of SQS-inhibition has been explored in preclinical studies demonstrating cooperation between SQS-inhibitors and statins in achieving increased LDL-cholesterol clearance 35 . Despite our findings supporting the efficacy of FDFT1 , there was also evidence of putative adverse side-effects.…”

Bovine Lactoferrin Inhibits Dengue Virus Infectivity by Interacting with Heparan Sulfate, Low-Density Lipoprotein Receptor, and DC-SIGN

“…Here, the anti-DENV-2 effect of bLF was attenuated by the addition of rLDLR. The LDLR are responsible for regulating the extracellular cholesterol concentration; cholesterol-lowering drugs such as statin increase LDLR expression, thereby reducing the serum cholesterol level [ 32 ]. Thus, a comprehensive study on the role of LDLR in DENV-2 infection and a risk assessment study to determine the effect of serum cholesterol level and dengue infection may be required to investigate the impact of cholesterol–lowering drugs on DENV infection.…”