Development of Light-Activated LXR Agonists

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.

Automated summary

Activation of local LXR may be a potential strategy for the treatment of metabolic diseases and cancer, and the development of photoswitchable LXR agonists based on the T0901317 scaffold can overcome the side effects of LXR agonists. The designed LXR agonist, activated in its light-induced state, sensitized human lung cancer cells to chemotherapy, supporting the potential of locally activated LXR agonists as adjuvant cancer treatment.