Development of Photoswitchable Estrogen Receptor Ligands

Tsuchiya, Keisuke; Umeno, Tomohiro; Genichiro, Tsuji; Yokoo, Hideyasu; Tanaka, Masakazu; Fukuhara, Kiyoshi; Demizu, Yosuke; Misawa, Takashi

doi:10.1248/cpb.c19-01108

Cited by 7 publications

(9 citation statements)

References 21 publications

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“…Subsequently, we developed a photohormone for the bile acid receptor farnesoid X receptor (FXR) that allows for the optical control of gene regulation in liver cells. In addition, a photoswitchable estrogen receptor (ER) agonist was recently reported by Tsuchiya. , Here, we disclose the development of photohormones for PPARγ, extending the reach of photopharmacology to another important member of the NHR superfamily.…”

Section: Introductionmentioning

confidence: 94%

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Photohormones Enable Optical Control of the Peroxisome Proliferator-Activated Receptor γ (PPARγ)

et al. 2020

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Photopharmacology aims at the optical control of protein activity using synthetic photoswitches. This approach has been recently expanded to nuclear hormone receptors with the introduction of "photohormones" for the retinoic acid receptor, farnesoid X receptor, and estrogen receptor. Herein, we report the development and profiling of photoswitchable agonists for peroxisome proliferator-activated receptor γ (PPARγ). Based on known PPARγ ligands (MDG548, GW1929, and rosiglitazone), we have designed and synthesized azobenzene derivatives, termed AzoGW1929 and AzoRosi, which were confirmed to be active in cell-based assays. Subsequent computer-aided optimization of AzoRosi resulted in the photohormone AzoRosi-4, which bound and activated PPARγ preferentially in its lightactivated cis-configuration.

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Section: Introductionmentioning

confidence: 94%

“…In addition, a photoswitchable estrogen receptor (ER) agonist was recently reported by Tsuchiya. 28,29 Here, we disclose the development of photohormones for PPARγ, extending the reach of photopharmacology to another important member of the NHR superfamily.…”

Section: ■ Introductionmentioning

confidence: 99%

Photohormones Enable Optical Control of the Peroxisome Proliferator-Activated Receptor γ (PPARγ)

et al. 2020

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“… [42] This photolipid successfully modulated FXR‐dependent gene expression in non‐transfected liver cells with light. Recently, a photoswitchable estrogen receptor ligand was developed ( 9 ) [43] . It exhibited different binding profiles in the presence and absence of UV‐A light as assayed by fluorescence polarization.…”

Section: Nuclear Hormone Receptorsmentioning

confidence: 99%

“…Recently, a photoswitchable estrogen receptor ligand was developed (9). [43] It exhibited different binding profiles in the presence and absence of UV-A light as assayed by fluorescence polarization.…”

Section: G Protein-coupled Receptorsmentioning

confidence: 99%

Photoswitchable Lipids

2020

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Photoswitchable lipids are emerging tools for the precise manipulation and study of lipid function. They can modulate many aspects of membrane biophysics, including permeability, fluidity, lipid mobility and domain formation. They are also very useful in lipid physiology and enable optical control of a wide array of lipid receptors, such as ion channels, G protein-coupled receptors, nuclear hormone receptors, and enzymes that trans-locate to membranes. Enzymes involved in lipid metabolism often process them in a light-dependent fashion. Photoswitchable lipids complement other functionalized lipids widely used in lipid chemical biology, including isotope-labeled lipids (lipidomics), fluorescent lipids (imaging), bifunctional lipids (lipid-protein crosslinking), photocaged lipids (photopharmacology), and other labeled variants.

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“…This could indeed be demonstrated with a few classes of NRs, including retinoic acid receptor α (RARα), which can be optically controlled by a photoswitchable retinoic acid derivative . Subsequently, we have developed dedicated photohormones for the bile acid-activated transcription factor farnesoid X receptor (FXR) and the fatty acid-sensing peroxisome proliferator-activated receptor γ (PPARγ), and Tsuchiya et al have reported a photoswitchable estrogen receptor (ER) agonist . Still, in light of their value as chemical tools for pharmacology, the collection of available photoswitchable ligands for transcription factors is scarce.…”

Section: Introductionmentioning

confidence: 99%

A Photohormone for Light-Dependent Control of PPARα in Live Cells

et al. 2021

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Photopharmacology enables the optical control of several biochemical processes using small-molecule photoswitches that exhibit different bioactivities in their cis-and transconformations. Such tool compounds allow for high spatiotemporal control of biological signaling, and the approach also holds promise for the development of drug molecules that can be locally activated to reduce target-mediated adverse effects. Herein, we present the expansion of the photopharmacological arsenal to two new members of the peroxisome proliferator-activated receptor (PPAR) family, PPARα and PPARδ. We have developed a set of highly potent PPARα and PPARδ targeting photohormones derived from the weak pan-PPAR agonist GL479 that can be deactivated by light. The photohormone 6 selectively activated PPARα in its trans-conformation with high selectivity over the related PPAR subtypes and was used in live cells to switch PPARα activity on and off in a light-and time-dependent fashion.

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Development of Photoswitchable Estrogen Receptor Ligands

Cited by 7 publications

References 21 publications

Photohormones Enable Optical Control of the Peroxisome Proliferator-Activated Receptor γ (PPARγ)

Photohormones Enable Optical Control of the Peroxisome Proliferator-Activated Receptor γ (PPARγ)

Photoswitchable Lipids

A Photohormone for Light-Dependent Control of PPARα in Live Cells

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