Sulindac-derived RXRα modulators inhibit cancer cell growth by binding to a novel site.
Retinoid X receptor-alpha (RXRα), an intriguing and unique drug target, can serve as an intracellular target mediating the anticancer effects of certain nonsteroidal anti-inflammatory drugs (NSAIDs), including sulindac. We report the synthesis and characterization of two sulindac analogs, K-8008 and K-8012, which exert improved anticancer activities over sulindac in a RXRα-dependent manner. The analogs inhibit the interaction of the N-terminally truncated RXRα (tRXRα) with the p85α subunit of PI3K, leading to suppression of AKT activation and induction of apoptosis. Crystal structures of the RXRα ligand-binding domain (LBD) with K-8008 or K-8012 reveal that both compounds bind to tetrameric RXRα LBD at a site different from the classical ligand-binding pocket. Thus, these results identify K-8008 and K-8012 as tRXRα modulators and define a binding mechanism for regulating the nongenomic action of tRXRα.
School of Pharmaceutical Sciences, Xiamen University, Xiamen 361102, China; Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
Liqun
L
Chen
Department of Chemistry and Fujian Provincial Key Laboratory of Chemical Biology, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen 361005, China.
Zhi-Gang
ZG
Wang
Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
Alexander E
AE
Aleshin
School of Pharmaceutical Sciences, Xiamen University, Xiamen 361102, China; Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
Fan
F
Chen
School of Pharmaceutical Sciences, Xiamen University, Xiamen 361102, China; Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
Jiebo
J
Chen
School of Pharmaceutical Sciences, Xiamen University, Xiamen 361102, China.
Fuquan
F
Jiang
School of Pharmaceutical Sciences, Xiamen University, Xiamen 361102, China.
Gulimiran
G
Alitongbieke
School of Pharmaceutical Sciences, Xiamen University, Xiamen 361102, China.
Zhiping
Z
Zeng
School of Pharmaceutical Sciences, Xiamen University, Xiamen 361102, China.
Yue
Y
Ma
School of Pharmaceutical Sciences, Xiamen University, Xiamen 361102, China.
Mingfeng
M
Huang
School of Pharmaceutical Sciences, Xiamen University, Xiamen 361102, China; Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
Hu
H
Zhou
Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
Gregory
G
Cadwell
Department of Chemistry and Fujian Provincial Key Laboratory of Chemical Biology, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen 361005, China.
Jian-Feng
JF
Zheng
Department of Chemistry and Fujian Provincial Key Laboratory of Chemical Biology, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen 361005, China.
Pei-Qiang
PQ
Huang
Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
Robert C
RC
Liddington
School of Pharmaceutical Sciences, Xiamen University, Xiamen 361102, China; Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA. Electronic address: xzhang@sanfordburnham.org.
Xiao-kun
XK
Zhang
School of Pharmaceutical Sciences, Xiamen University, Xiamen 361102, China; Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA. Electronic address: ysu@sanfordburnham.org.
Ying
Y
Su
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D001665:Binding Sites / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006367:HeLa Cells; D056945:Hep G2 Cells; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008958:Models, Molecular; D015394:Molecular Structure; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D047490:Retinoid X Receptor alpha / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013467:Sulindac / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D047490:Retinoid X Receptor alpha; D013467:Sulindac