Evaluating Novel RXR Agonists That Induce ApoE and Tyrosine Hydroxylase in Cultured Human Glioblastoma Cells

Abstract

There is considerable interest in identifying effective and safe drugs for neurodegenerative disorders. Cell culture and animal model work have demonstrated that modulating gene expression through RXR-mediated pathways may mitigate or reverse cognitive decline. However, because RXR is a dimeric partner for several transcription factors, activating off-target transcription is a concern with RXR ligands (rexinoids). This off-target gene modulation leads to unwanted side effects that can include low thyroid function and significant hyperlipidemia. There is a need to develop rexinoids that have binding specificity for subsets of RXR heterodimers, to drive desired gene modulation, but that do not induce spurious effects. Herein, we describe experiments in which we analyze a series of novel and previously reported rexinoids for their ability to modulate specific gene pathways implicated in neurodegenerative disorders employing a U87 cell culture model. We demonstrate that, compared to the FDA-approved rexinoid bexarotene (1), several of these compounds are equally or more effective at stimulating gene expression via LXREs or Nurr1/NBREs and are superior at inducing ApoE and/or tyrosine hydroxylase (TH) gene and protein expression, including analogs 8, 9, 13, 14, 20, 23, and 24, suggesting a possible therapeutic role for these compounds in Alzheimer's or Parkinson's disease (PD). A subset of these potent RXR agonists can synergize with a presumed Nurr1 ligand and antimalarial drug (amodiaquine) to further enhance Nurr1/NBREs-directed transcription. This novel discovery has potential clinical implications for treatment of PD since it suggests that the combination of an RXR agonist and a Nurr1 ligand can significantly enhance RXR-Nurr1 heterodimer activity and drive enhanced therapeutic expression of the TH gene to increase endogenous synthesis of dopamine. These data indicate that is it possible and prudent to develop novel rexinoids for testing of gene expression and side effect profiles for use in potential treatment of neurodegenerative disorders, as individual rexinoids can have markedly different gene expression profiles but similar structures.

The rexinoid V-125 reduces tumor growth in preclinical models of breast and lung cancer

“…We have found that applying principal component analysis (PCA) in our prior work 35 , 36 with rexinoids has helped to visualize particularly active rexinoids with improved therapeutic potential, and to that end, we have conducted a PCA with V-125 and the nine other novel rexinoids (Fig. 1 ) to visualize where they group relative to each other as well as bexarotene and LG100268 (Figs.…”

“…S1 and S2 to analyze compounds for biological activity motifs. Ellipses in the PCA indicate 95% confidence intervals 35 , 36 .…”

Late‐Stage Borylation Strategy for the Development of New Boron‐Based Retinoids

“…However, it has been realized that bexarotene is limited by side‐effects including hyperlipidemia, hypothyroidism, and cutaneous toxicity. The side effects are likely due to disruption of nonpermissive receptor activation by RXR‐TR heterodimers, stimulation of permissive activation by RXR‐LXR, or activation of RXR‐RAR [5] . Therefore, developing novel RXR agonists that may overcome these side effects is a highly worthwhile pursuit.…”

“…The side effects are likely due to disruption of nonpermissive receptor activation by RXR-TR heterodimers, stimulation of permissive activation by RXR-LXR, or activation of RXR-RAR. [5] Therefore, developing novel RXR agonists that may overcome these side effects is a highly worthwhile pursuit.…”

Modeling, Synthesis, and Biological Evaluation of Potential Retinoid-X-Receptor (RXR) Selective Agonists: Analogs of 4-[1-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahyro-2-naphthyl)ethynyl]benzoic Acid (Bexarotene) and 6-(Ethyl(4-isobutoxy-3-isopropylphenyl)amino)nicotinic Acid (NEt-4IB)

“…Adding to the urgency of developing novel rexinoids possessing attenuated side effect profiles, compound 1 has shown some promise in neurodegenerative disease models such as Parkinson's disease [39] and Alzheimer's disease (AD) [40]. Moreover, several novel rexinoids were recently reported to be equally or more effective at modulating gene expression on LXREs and NBREs and are thus superior at inducing ApoE and tyrosine hydroxylase, two genes whose enhanced expression is thought to mitigate the pathophysiology associated with Parkinson's and Alzheimer's diseases [41]. Significantly, a POC trial of 1 in AD patients exhibiting moderate symptoms demonstrated a statistically significant clearance of soluble amyloid beta in non-apoE 4 genotypes [42].…”