Faculty Collaboration Database

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). Int J Mol Sci 2021 Nov 16;22(22)

Date

11/28/2021

Pubmed ID

34830251

Pubmed Central ID

PMC8624485

DOI

10.3390/ijms222212371

Scopus ID

2-s2.0-85119007925 (requires institutional sign-in at Scopus site)   2 Citations

Abstract

Five novel analogs of 6-(ethyl)(4-isobutoxy-3-isopropylphenyl)amino)nicotinic acid-or NEt-4IB-in addition to seven novel analogs of 4-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethynyl]benzoic acid (bexarotene) were prepared and evaluated for selective retinoid-X-receptor (RXR) agonism alongside bexarotene (1), a FDA-approved drug for cutaneous T-cell lymphoma (CTCL). Bexarotene treatment elicits side-effects by provoking or disrupting other RXR-dependent pathways. Analogs were assessed by the modeling of binding to RXR and then evaluated in a human cell-based RXR-RXR mammalian-2-hybrid (M2H) system as well as a RXRE-controlled transcriptional system. The analogs were also tested in KMT2A-MLLT3 leukemia cells and the EC₅₀ and IC₅₀ values were determined for these compounds. Moreover, the analogs were assessed for activation of LXR in an LXRE system as drivers of ApoE expression and subsequent use as potential therapeutics in neurodegenerative disorders, and the results revealed that these compounds exerted a range of differential LXR-RXR activation and selectivity. Furthermore, several of the novel analogs in this study exhibited reduced RARE cross-signaling, implying RXR selectivity. These results demonstrate that modification of partial agonists such as NEt-4IB and potent rexinoids such as bexarotene can lead to compounds with improved RXR selectivity, decreased cross-signaling of other RXR-dependent nuclear receptors, increased LXRE-heterodimer selectivity, and enhanced anti-proliferative potential in leukemia cell lines compared to therapeutics such as 1.

Author List

Jurutka PW, di Martino O, Reshi S, Mallick S, Sabir ZL, Staniszewski LJP, Warda A, Maiorella EL, Minasian A, Davidson J, Ibrahim SJ, Raban S, Haddad D, Khamisi M, Suban SL, Dawson BJ, Candia R, Ziller JW, Lee MY, Liu C, Liu W, Marshall PA, Welch JS, Wagner CE

Author

Wei Liu PhD Associate Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Antineoplastic Agents
Apolipoproteins E
Cell Line, Tumor
Dose-Response Relationship, Drug
Gene Expression
Humans
Leukocytes
Nicotinic Acids
Retinoid X Receptor alpha
Structure-Activity Relationship