Development of Light-Activated LXR Agonists
Tufan K Mukhopadhyay1, Sabine Willems2, Christopher J Arp1
1Department of Chemistry, New York University, New York City, NY, 10003, USA.
Abstract:
Activation of the oxysterol-sensing transcription factor liver X receptor (LXR) has been studied as a therapeutic strategy in metabolic diseases and cancer but is compromised by the side effects of LXR agonists. Local LXR activation in cancer treatment may offer an opportunity to overcome this issue suggesting potential uses of photopharmacology. We report the computer-aided development of photoswitchable LXR agonists based on the T0901317 scaffold, which is a known LXR agonist. Azologization and structure-guided structure-activity relationship evaluation enabled the design of an LXR agonist, which activated LXR with low micromolar potency in its light-induced (Z)-state and was inactive as (E)-isomer. This tool sensitized human lung cancer cells to chemotherapeutic treatment in a light-dependent manner supporting potential of locally activated LXR agonists as adjuvant cancer treatment.
Insights
Researchers developed photoswitchable liver X receptor (LXR) agonists for targeted cancer therapy. These compounds activate LXR with light, enhancing chemotherapy efficacy in lung cancer cells while minimizing side effects.
Area of Science:
- Medicinal Chemistry
- Molecular Pharmacology
- Cancer Therapeutics
Background:
- Liver X receptor (LXR) activation is a therapeutic strategy for metabolic diseases and cancer.
- Current LXR agonists cause side effects, limiting their clinical use.
- Photopharmacology offers potential for localized LXR activation to mitigate side effects.
Purpose of the Study:
- To design and develop photoswitchable liver X receptor (LXR) agonists.
- To investigate the potential of these compounds as adjuvant cancer therapy.
- To create a tool for light-dependent LXR activation in cancer cells.
Main Methods:
- Computer-aided drug design based on the T0901317 scaffold.
- Azologization and structure-activity relationship (SAR) evaluation.
- Testing of photoswitchable LXR agonists in human lung cancer cells.
Main Results:
- A novel photoswitchable LXR agonist was developed, active in its (Z)-isomer upon light induction.
- The compound showed low micromolar potency for LXR activation.
- Light-dependent sensitization of human lung cancer cells to chemotherapeutic treatment was observed.
Conclusions:
- Photoswitchable LXR agonists represent a promising strategy for targeted cancer therapy.
- Local activation of LXR via photopharmacology can enhance chemotherapy efficacy.
- This approach may overcome the limitations of systemic LXR agonist administration.
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