2. Academic Validation
  3. Sulindac-derived RXRα modulators inhibit cancer cell growth by binding to a novel site

Sulindac-derived RXRα modulators inhibit cancer cell growth by binding to a novel site

  • Chem Biol. 2014 May 22;21(5):596-607. doi: 10.1016/j.chembiol.2014.02.017.
Liqun Chen 1,  Zhi-Gang Wang 2,  Alexander E Aleshin 3,  Fan Chen 1,  Jiebo Chen 1,  Fuquan Jiang 4,  Gulimiran Alitongbieke 4,  Zhiping Zeng 4,  Yue Ma 4,  Mingfeng Huang 4,  Hu Zhou 1,  Gregory Cadwell 3,  Jian-Feng Zheng 2,  Pei-Qiang Huang 2,  Robert C Liddington 3,  Xiao-kun Zhang 5,  Ying Su 6
Affiliations

Affiliations

  • 1 School of Pharmaceutical Sciences, Xiamen University, Xiamen 361102, China; Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
  • 2 Department of Chemistry and Fujian Provincial Key Laboratory of Chemical Biology, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen 361005, China.
  • 3 Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
  • 4 School of Pharmaceutical Sciences, Xiamen University, Xiamen 361102, China.
  • 5 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.
  • 6 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.
PMID: 24704507 DOI: 10.1016/j.chembiol.2014.02.017
Abstract

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.

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