Modification at the acidic domain of RXR agonists has little effect on permissive RXR-heterodimer activation

Fujii, Satoshi; Ohsawa, Fuminori; Yamada, Shoya; Shinozaki, Ryosuke; Fukai, Ryosuke; Makishima, Makoto; Enomoto, Shuichi; Tai, Akihiro; Kakuta, Hiroki

doi:10.1016/j.bmcl.2010.07.012

Cited by 29 publications

(34 citation statements)

References 27 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The incorporation of alkoxy groups at the lipophilic region led to a series of rexinoids, such as the cyclopropylmethyloxy analogue 11.4, with selectivity for activation of PPAR /RXR vs LXR /RXR heterodimers [96]. Modification of the acidic domain by replacing the carboxylic acid of 11.3 by phosphonic acid, tetrazole and hydroxamic acid have little effect on permissive RXR heterodimer activation [97]. Both activate PPAR /RXR heterodimers, but only PA024 11.3a activates LXR/RXR and ABCA1 promoter.…”

Section: Retinoid Synergistsmentioning

confidence: 98%

Retinoid Receptors and Therapeutic Applications of RAR/RXR Modulators

Maire¹,

Álvarez²,

Shankaranarayanan³

et al. 2012

CTMC

View full text Add to dashboard Cite

Retinoic acid receptors (RARs) are ligand-controlled transcription factors that function as heterodimers with retinoid X receptors (RXRs) to regulate cell growth, differentiation, survival and death. Due to their regulatory potential, these nuclear receptors (NRs) are major drug targets for a variety of pathologies, including cancer and metabolic diseases. A large amount of RAR- and RXR-selective ligands, ranging from (partial) agonists to antagonists and inverse agonists, have been designed and the corresponding structural and functional analyses have provided deep insight into the molecular basis of ligand action. Ligands regulate, via allosteric conformational changes, the ability of these NRs to interact with different sets of coregulators, which in turn recruit enzymatically active complexes/machineries. Here, we describe strategies in the design of selective RXR and RAR modulators and review the structural mechanisms by which the diverse pharmacological classes of compounds modulate receptor functions. Finally, we discuss the perspectives for retinoid- and rexinoid-based therapies.

show abstract

Section: Retinoid Synergistsmentioning

confidence: 98%

Retinoid Receptors and Therapeutic Applications of RAR/RXR Modulators

Maire¹,

Álvarez²,

Shankaranarayanan³

et al. 2012

CTMC

View full text Add to dashboard Cite

show abstract

“…It was also reported that modification or replacement of the carboxyl group in the acidic moiety of rexinoids had little or no effects on permissive RXR heterodimers activation. 33 It was thus suggested that the end side of the pocket for the acidic moiety binding, consisting of Gln275 in H3; Trp305, Asn306, and Arg316 in H5; Ile324, Leu325, Leu326, and Ala327 in β-sheet S1; and Leu451 in H12, might not be potent for RXRα activation.…”

Section: Crystal Structure Revealed a Distinct Binding Mode For Bigelmentioning

confidence: 99%

“…1 Interestingly, the patterns of RXRα-involved heterodimeric activation seemed to be related to the chemical structures of RXR agonists, although the structure-activity relationship is still elusive. 33,34 It was suggested that ligand-dependent allosteric alterations changed the ability of RXR to communicate with its heterodimeric partners in a mutual fashion, thus regulating the activities of the transcriptional machineries. 2,6 Activation of PPARγ could cause apoptosis in cancer cells.…”

Section: Bigelovin Was a Selective Rxrα Agonistmentioning

confidence: 99%

Structure Basis of Bigelovin as a Selective RXR Agonist with a Distinct Binding Mode

Zhang

Chen

et al. 2011

Journal of Molecular Biology

View full text Add to dashboard Cite

“…In vitro this compound activated selectively the RXRa-PPARg and RXRa-LXRa heterodimers but to a lesser extent than agonist NEt-TMN 5.4f. Finally, the replacement of the carboxylic acid by phosphonic acid, tetrazole and hydroxamic acid had little effect on permissive RXR heterodimer activation within this series [80]. Also belonging to this group is the aminopyrimidine derivative XCT0135908 5.9 (discovered by screening of a chemical library), a rexinoid that highly selectively activated the RXRNurr1 heterodimers in African green monkey CV-1 cells [31].…”

Section: Structure-based Design Of Rexinoid Modulatorsmentioning

confidence: 99%