An Isochroman Analog of CD3254 and Allyl-, Isochroman-Analogs of NEt-TMN Prove to Be More Potent Retinoid-X-Receptor (RXR) Selective Agonists Than Bexarotene

Abstract

Bexarotene is an FDA-approved drug for the treatment of cutaneous T-cell lymphoma (CTCL); however, its use provokes or disrupts other retinoid-X-receptor (RXR)-dependent nuclear receptor pathways and thereby incites side effects including hypothyroidism and raised triglycerides. Two novel bexarotene analogs, as well as three unique CD3254 analogs and thirteen novel NEt-TMN analogs, were synthesized and characterized for their ability to induce RXR agonism in comparison to bexarotene (1). Several analogs in all three groups possessed an isochroman ring substitution for the bexarotene aliphatic group. Analogs were modeled for RXR binding affinity, and EC50 as well as IC50 values were established for all analogs in a KMT2A-MLLT3 leukemia cell line. All analogs were assessed for liver-X-receptor (LXR) activity in an LXRE system to gauge the potential for the compounds to provoke raised triglycerides by increasing LXR activity, as well as to drive LXRE-mediated transcription of brain ApoE expression as a marker for potential therapeutic use in neurodegenerative disorders. Preliminary results suggest these compounds display a broad spectrum of off-target activities. However, many of the novel compounds were observed to be more potent than 1. While some RXR agonists cross-signal the retinoic acid receptor (RAR), many of the rexinoids in this work displayed reduced RAR activity. The isochroman group did not appear to substantially reduce RXR activity on its own. The results of this study reveal that modifying potent, selective rexinoids like bexarotene, CD3254, and NEt-TMN can provide rexinoids with increased RXR selectivity, decreased potential for cross-signaling, and improved anti-proliferative characteristics in leukemia models compared to 1.

Rexinoids Induce Differential Gene Expression in Human Glioblastoma Cells and Protein–Protein Interactions in a Yeast Two-Hybrid System

“…Bexarotene is a high-affinity ligand for RXR, which can elicit heterodimerization to form RXR-LXR and/or RXR-PPARγ to control cholesterol efflux, inflammation, and to transcriptionally upregulate the production of apolipoprotein (ApoE) in the brain . Enhanced ApoE expression may promote clearance of soluble Aβ peptides from the brain and reduce Aβ plaques, thus resolving both amyloid pathology and cognitive deficits …”

Structural Fusion of Natural and Synthetic Ligand Features Boosts RXR Agonist Potency

“…Similarly, the natural product valerenic acid (3), which has been discovered in a virtual screening as RXRβ agonist with functional preference over RXRα and RXRγ, 22 contains an αmethylacrylic acid substructure. We hypothesized that the (substituted) acrylate motif occurring in natural RXR ligands might be favored in terms of RXR agonist potency and probed its fusion (A) with two validated synthetic RXR ligand scaffolds�indanyloxymethylphenylpropanoic acid (4), which has been discovered as an RXR ligand chemotype enabling subtype preference, 23 and oxaprozin (17), which has offered access to RXR agonists with highly favorable properties. 24 While no substantial improvement was achieved by this approach with the scaffold of 4, the structural fusion of natural and synthetic ligand features was particularly successful with the RXR agonist chemotype of oxaprozin (17).…”

“…We hypothesized that the (substituted) acrylate motif occurring in natural RXR ligands might be favored in terms of RXR agonist potency and probed its fusion (A) with two validated synthetic RXR ligand scaffolds�indanyloxymethylphenylpropanoic acid (4), which has been discovered as an RXR ligand chemotype enabling subtype preference, 23 and oxaprozin (17), which has offered access to RXR agonists with highly favorable properties. 24 While no substantial improvement was achieved by this approach with the scaffold of 4, the structural fusion of natural and synthetic ligand features was particularly successful with the RXR agonist chemotype of oxaprozin (17). Introduction of the α-methylacrylic acid motif in 17 produced a marked increase in potency, confirming the potential of this residue to drive RXR agonism.…”

“…The nuclear retinoid X receptors (RXRα, RXRβ, RXRγ; NR2B1–3) regulate gene expression in response to ligands like 9-cis retinoic acid ( 1 , Chart ) and other fatty acids. − Due to their central role in nuclear receptor signaling as a universal heterodimer partner, RXRs are widely distributed over all tissues and linked to multiple pathologies including metabolic and inflammatory diseases, cancer, and neurodegeneration. ,,− Despite offering remarkable therapeutic potential in these various diseases, pharmacological RXR modulation is restricted by the lack of safe RXR agonists. ,, Bexarotene ( 2 ), holding approval for second-line indications in cancer treatment, is the only synthetic RXR agonist on the drug market but associated with adverse effects. − Lack of selectivity for RXR − and poor physicochemical features and pharmacokinetics , hinder the use of 2 in further therapeutic areas and also question its broad use as a reference RXR ligand . Next-generation RXR agonists with improved properties and selectivity are needed as tools to capture and exploit the unexplored therapeutic potential of RXR.…”

Novel Strategies in the Development of New Therapies, Drug Substances, and Drug Carriers Volume II

“…Bexarotene, a drug that is active against cutaneous T-cell lymphoma, interferes with retinoid X-receptor (RXR)-dependent pathways and might cause serious side effects such as hypothyroidism. Therefore, Jurutka et al [ 4 ] synthesized analogs of this drug, aiming to retain its key function and avoid harmful side effects. The bexarotene alicyclic ring, aliphatic linker, and benzoic acid moiety were substituted with an isochroman ring and nitrogen heterocycles, respectively.…”