TY - JOUR
T1 - Modeling, synthesis and biological evaluation of potential retinoid‐x‐receptor (Rxr) selective agonists
T2 - 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)
AU - Jurutka, Peter W.
AU - Di Martino, Orsola
AU - Reshi, Sabeeha
AU - Mallick, Sanchita
AU - Sabir, Zhela L.
AU - Staniszewski, Lech J.P.
AU - Warda, Ankedo
AU - Maiorella, Emma L.
AU - Minasian, Ani
AU - Davidson, Jesse
AU - Ibrahim, Samir J.
AU - Raban, San
AU - Haddad, Dena
AU - Khamisi, Madleen
AU - Suban, Stephanie L.
AU - Dawson, Bradley J.
AU - Candia, Riley
AU - Ziller, Joseph W.
AU - Lee, Ming Yue
AU - Liu, Chang
AU - Liu, Wei
AU - Marshall, Pamela A.
AU - Welch, John S.
AU - Wagner, Carl E.
N1 - Funding Information:
Acknowledgments: Thanks are given to Felix Grun of the High‐Resolution Mass Spectrometry La‐ boratory at University of California, Irvine (UCI). We thank Gayla Hadwiger and Anh Vu for tech‐ nical support. We thank the Alvin J. Siteman Cancer Center at Washington University School of Medicine for the use of the Flow Cytometry Core. The Siteman Cancer Center is supported in part by an NCI Cancer Center Support Grant P30 CA91842.
Funding Information:
Funding: This research was funded by the U.S. National Institutes of Health, grant number 1 R15 CA139364‐01A2 and 1R15CA249617‐01 to C.E.W., P.W.J. and P.A.M; by R01 HL128447 to J.S.W; and by the Siteman Investment Program to J.S.W.
Funding Information:
This research was funded by the U.S. National Institutes of Health, grant number 1 R15 CA139364?01A2 and 1R15CA249617?01 to C.E.W., P.W.J. and P.A.M; by R01 HL128447 to J.S.W; and by the Siteman Investment Program to J.S.W.
Publisher Copyright:
© 2021 by the author. Licensee MDPI, Basel, Switzerland.
PY - 2021/11/1
Y1 - 2021/11/1
N2 - 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.
AB - 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.
KW - Leukemia
KW - Retinoid
KW - Retinoid‐X‐receptor
KW - Rexinoid
KW - Small molecule therapeutic
KW - Structure– activity relationship
UR - http://www.scopus.com/inward/record.url?scp=85119007925&partnerID=8YFLogxK
U2 - 10.3390/ijms222212371
DO - 10.3390/ijms222212371
M3 - Article
C2 - 34830251
AN - SCOPUS:85119007925
SN - 1661-6596
VL - 22
JO - International journal of molecular sciences
JF - International journal of molecular sciences
IS - 22
M1 - 12371
ER -