Christopher J. Arp

Somatosensory neurons (SSNs) that detect and transduce mechanical, thermal, and chemical stimuli densely innervate an animal’s skin. However, although epidermal cells provide the first point of contact for sensory stimuli, our understanding of roles that epidermal cells play in SSN function, particularly nociception, remains limited. Here, we show that stimulating Drosophila epidermal cells elicits activation of SSNs including nociceptors and triggers a variety of behavior outputs, including avoidance and escape. Further, we find that epidermal cells are intrinsically mechanosensitive and that epidermal mechanically evoked calcium responses require the store-operated calcium channel Orai. Epidermal cell stimulation augments larval responses to acute nociceptive stimuli and promotes prolonged hypersensitivity to subsequent mechanical stimuli. Hence, epidermal cells are key determinants of nociceptive sensitivity and sensitization, acting as primary sensors of noxious stimuli that tune nociceptor output and drive protective behaviors.

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.

Immunomodulatory drugs (IMiDs), which include thalidomide and its derivatives, have emerged as the standard of care against multiple myeloma. They function as molecular glues that bind to the E3 ligase cereblon (CRBN) and induce protein interactions with neosubstrates, including the transcription factors Ikaros (IKZF1) and Aiolos (IKZF3). The subsequent ubiquitylation and degradation of these transcription factors underlies the antiproliferative activity of IMiDs. Here, we introduce photoswitchable immunomodulatory drugs (PHOIMiDs) that can be used to degrade Ikaros and Aiolos in a light-dependent fashion. Our lead compound shows minimal activity in the dark and becomes an active degrader upon irradiation with violet light. It shows high selectivity over other transcription factors, regardless of its state, and could therefore be used to control the levels of Ikaros and Aiolos with high spatiotemporal precision.

Article published online: 15 June 2022 © 2022. Thieme. All rights reserved Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart, Germany

Publication Date: 17 May 2022 (online) © 2022. Thieme. All rights reserved Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart, Germany