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

被引：5

作者：

Atigadda, Venkatram R. ^{[1
]}

Kashyap, Mahendra P. ^{[1
]}

Yang, Zhengrong ^{[2
]}

Chattopadhyay, Debasish ^{[3
]}

Melo, Nathalia ^{[2
]}

Sinha, Rajesh ^{[1
]}

V. Belyaeva, Olga ^{[2
]}

Chou, Chu-Fang ^{[4
]}

Chang, Pi-Ling ^{[4
]}

Kedishvili, Natalia Y. ^{[2
]}

Grubbs, Clinton J. ^{[5
]}

Renfrow, Matthew B. ^{[2
]}

Muccio, Donald D. ^{[2
]}

Elmets, Craig A. ^{[1
]}

Athar, Mohammad ^{[1
]}

机构：

[1] Univ Alabama Birmingham, Dept Dermatol, Birmingham, AL 35294 USA

[2] Univ Alabama Birmingham, Biochem & Mol Genet, Birmingham, AL 35294 USA

[3] Univ Alabama Birmingham, Med, Birmingham, AL 35294 USA

[4] Univ Alabama Birmingham, Nutr Sci, Birmingham, AL 35294 USA

[5] Univ Alabama Birmingham, Surg, Birmingham, AL 35294 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2022年 / 65卷 / 21期

基金：

美国国家卫生研究院;

关键词：

LIGAND-BINDING DOMAIN; ORAL BEXAROTENE; MAMMARY CANCERS; EFFICACY; AGONIST; TARGRETIN; THERAPY; UAB30;

D O I：

10.1021/acs.jmedchem.2c00735

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Compound 1 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 1, we synthesized four new analogs of rexinoid 1, of which three rexinoids did not elevate serum triglycerides. Rexinoids 3 and 4 are twice as potent as rexinoid 1 in binding to Retinoid X receptor (RXR). All-trans retinoic acid (ATRA) plays a key role in maintaining skin homeostasis, and rexinoids 3-6 are highly effective in upregulating the genes responsible for the biosynthesis of ATRA. Inflammation plays a key role in skin cancer, and rexinoids 3 and 4 are highly effective in diminishing LPS-induced inflammation. Rexinoids 3 and 4 are highly effective in preventing UVB-induced nonmelanoma skin cancer (NMSC) without displaying any overt toxicities. Biophysical studies of rexinoids 3 and 5 bound to hRXR alpha-ligand binding domain (LBD) reveal important conformational and dynamical differences in the ligand binding domain.

引用

页码：14409 / 14423

页数：15

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