Conformationally Defined Rexinoids for the Prevention of Inflammation and Nonmelanoma Skin Cancers

Overview

Journal J Med Chem

Publisher American Chemical Society

Specialty Chemistry

Date 2022 Nov 1

PMID 36318154

Authors

Venkatram R Atigadda

Mahendra P Kashyap

Zhengrong Yang

Debasish Chattopadhyay

Nathalia Melo

Rajesh Sinha

Olga V Belyaeva

Chu-Fang Chou

Pi-Ling Chang

Natalia Y Kedishvili

Clinton J Grubbs

Matthew B Renfrow

Donald D Muccio

Craig A Elmets

Mohammad Athar

Affiliations

Soon will be listed here.

Abstract

Compound is a potent rexinoid that is highly effective in cancer chemoprevention but elevates serum triglycerides. In an effort to separate the lipid toxicity from the anticancer activity of , we synthesized four new analogs of rexinoid , of which three rexinoids did not elevate serum triglycerides. Rexinoids and are twice as potent as rexinoid in binding to Retinoid X receptor (RXR). retinoic acid (ATRA) plays a key role in maintaining skin homeostasis, and rexinoids are highly effective in upregulating the genes responsible for the biosynthesis of ATRA. Inflammation plays a key role in skin cancer, and rexinoids and are highly effective in diminishing LPS-induced inflammation. Rexinoids and are highly effective in preventing UVB-induced nonmelanoma skin cancer (NMSC) without displaying any overt toxicities. Biophysical studies of rexinoids and bound to hRXRα-ligand binding domain (LBD) reveal important conformational and dynamical differences in the ligand binding domain.

Citing Articles

Ultraviolet (UV) radiation: a double-edged sword in cancer development and therapy.

Yu Z, Zheng M, Fan H, Liang X, Tang Y Mol Biomed. 2024; 5(1):49.

PMID: 39417901 PMC: 11486887. DOI: 10.1186/s43556-024-00209-8.

Retinoid X Receptor agonists as selective modulators of the immune system for the treatment of cancer.

Leal A, Hung P, Chowdhury A, Liby K Pharmacol Ther. 2023; 252:108561.

PMID: 37952906 PMC: 10704405. DOI: 10.1016/j.pharmthera.2023.108561.

Retinoid X Receptor Activation Prevents Diabetic Retinopathy in Murine Models.

Dorofeeva I, Zhylkibayev A, Saltykova I, Atigadda V, Adhikari B, Gorbatyuk O Cells. 2023; 12(19).

PMID: 37830574 PMC: 10571672. DOI: 10.3390/cells12192361.

References

Desphande A, Xia G, Boerma L, Vines K, Atigadda V, Lobo-Ruppert S . Methyl-substituted conformationally constrained rexinoid agonists for the retinoid X receptors demonstrate improved efficacy for cancer therapy and prevention. Bioorg Med Chem. 2013; 22(1):178-85. PMC: 4387854. DOI: 10.1016/j.bmc.2013.11.039. View

Sobolev V, Sorokine A, Prilusky J, Abola E, Edelman M . Automated analysis of interatomic contacts in proteins. Bioinformatics. 1999; 15(4):327-32. DOI: 10.1093/bioinformatics/15.4.327. View

Wang L, Yi T, Kortylewski M, Pardoll D, Zeng D, Yu H . IL-17 can promote tumor growth through an IL-6-Stat3 signaling pathway. J Exp Med. 2009; 206(7):1457-64. PMC: 2715087. DOI: 10.1084/jem.20090207. View

Djurec M, Grana O, Lee A, Troule K, Espinet E, Cabras L . Saa3 is a key mediator of the protumorigenic properties of cancer-associated fibroblasts in pancreatic tumors. Proc Natl Acad Sci U S A. 2018; 115(6):E1147-E1156. PMC: 5819438. DOI: 10.1073/pnas.1717802115. View

Chagani S, Wang R, Carpenter E, Lohr C, Ganguli-Indra G, Indra A . Ablation of epidermal RXRα in cooperation with activated CDK4 and oncogenic NRAS generates spontaneous and acute neonatal UVB induced malignant metastatic melanomas. BMC Cancer. 2017; 17(1):736. PMC: 5679438. DOI: 10.1186/s12885-017-3714-6. View

Brunger A, Adams P, Clore G, DeLano W, Gros P, Grosse-Kunstleve R . Crystallography & NMR system: A new software suite for macromolecular structure determination. Acta Crystallogr D Biol Crystallogr. 1998; 54(Pt 5):905-21. DOI: 10.1107/s0907444998003254. View

Roos T, Jugert F, Merk H, Bickers D . Retinoid metabolism in the skin. Pharmacol Rev. 1998; 50(2):315-33. View

Dheer Y, Chitranshi N, Gupta V, Sharma S, Pushpitha K, Abbasi M . Retinoid x receptor modulation protects against ER stress response and rescues glaucoma phenotypes in adult mice. Exp Neurol. 2019; 314:111-125. DOI: 10.1016/j.expneurol.2019.01.015. View

Greuter T, Vavricka S, Konig A, Beaugerie L, Scharl M . Malignancies in Inflammatory Bowel Disease. Digestion. 2020; 101 Suppl 1:136-145. DOI: 10.1159/000509544. View

10.

Alam J, Yu Z, de Paiva C, Pflugfelder S . Retinoid Regulation of Ocular Surface Innate Inflammation. Int J Mol Sci. 2021; 22(3). PMC: 7866051. DOI: 10.3390/ijms22031092. View

11.

Atigadda V, Vines K, Grubbs C, Hill D, Beenken S, Bland K . Conformationally defined retinoic acid analogues. 5. Large-scale synthesis and mammary cancer chemopreventive activity for (2E,4E,6Z,8E)-8-(3',4'-dihydro-1'(2'H)-naphthalen-1'-ylidene)-3,7-dimethyl-2,4,6-octatrienoic acid (9cUAB30). J Med Chem. 2003; 46(17):3766-9. DOI: 10.1021/jm030095q. View

12.

Atigadda V, Xia G, Desphande A, Boerma L, Lobo-Ruppert S, Grubbs C . Methyl substitution of a rexinoid agonist improves potency and reveals site of lipid toxicity. J Med Chem. 2014; 57(12):5370-80. PMC: 4216212. DOI: 10.1021/jm5004792. View

13.

Grubbs C, Lubet R, Atigadda V, Christov K, Deshpande A, Tirmal V . Efficacy of new retinoids in the prevention of mammary cancers and correlations with short-term biomarkers. Carcinogenesis. 2005; 27(6):1232-9. DOI: 10.1093/carcin/bgi308. View

14.

Xia G, Boerma L, Cox B, Qiu C, Kang S, Smith C . Structure, energetics, and dynamics of binding coactivator peptide to the human retinoid X receptor α ligand binding domain complex with 9-cis-retinoic acid. Biochemistry. 2010; 50(1):93-105. PMC: 3081989. DOI: 10.1021/bi101288y. View

15.

Athar M, Li C, Kim A, Spiegelman V, Bickers D . Sonic hedgehog signaling in Basal cell nevus syndrome. Cancer Res. 2014; 74(18):4967-75. PMC: 4167483. DOI: 10.1158/0008-5472.CAN-14-1666. View

16.

McGowan M, Artiss J, Strandbergh D, ZAK B . A peroxidase-coupled method for the colorimetric determination of serum triglycerides. Clin Chem. 1983; 29(3):538-42. View

17.

Cheng L, Norris A, Tate B, Rosenberger M, Grippo J, Li E . Characterization of the ligand binding domain of human retinoid X receptor alpha expressed in Escherichia coli. J Biol Chem. 1994; 269(28):18662-7. View

18.

Kolesar J, Andrews S, Green H, Havighurst T, Wollmer B, DeShong K . A Randomized, Placebo-Controlled, Double-Blind, Dose Escalation, Single Dose, and Steady-State Pharmacokinetic Study of 9cUAB30 in Healthy Volunteers. Cancer Prev Res (Phila). 2019; 12(12):903-912. PMC: 7008944. DOI: 10.1158/1940-6207.CAPR-19-0310. View

19.

Kapetanovic I, Horn T, Johnson W, Cwik M, Detrisac C, McCormick D . Murine oncogenicity and pharmacokinetics studies of 9-cis-UAB30, an RXR agonist, for breast cancer chemoprevention. Int J Toxicol. 2010; 29(2):157-64. DOI: 10.1177/1091581809360070. View

20.

Gupta R, DuBois R . Colorectal cancer prevention and treatment by inhibition of cyclooxygenase-2. Nat Rev Cancer. 2002; 1(1):11-21. DOI: 10.1038/35094017. View