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)

Peter W. Jurutka, Orsola Di Martino, Sabeeha Reshi, Sanchita Mallick, Zhela L. Sabir, Lech J.P. Staniszewski, Ankedo Warda, Emma L. Maiorella, Ani Minasian, Jesse Davidson, Samir J. Ibrahim, San Raban, Dena Haddad, Madleen Khamisi, Stephanie L. Suban, Bradley J. Dawson, Riley Candia, Joseph W. Ziller, Ming Yue Lee, Chang LiuWei Liu, Pamela A. Marshall, John S. Welch, Carl E. Wagner

Research output: Contribution to journalArticlepeer-review

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‐Xreceptor (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.

Original languageEnglish (US)
Article number12371
JournalInternational journal of molecular sciences
Volume22
Issue number22
DOIs
StatePublished - Nov 1 2021
Externally publishedYes

Keywords

  • Leukemia
  • Retinoid
  • Retinoid‐X‐receptor
  • Rexinoid
  • Small molecule therapeutic
  • Structure– activity relationship

ASJC Scopus subject areas

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry

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