Rikken Gijs, Smith Kayla J, van den Brink Noa J M, Smits Jos P H, Gowda Krishne, Alnemri Angela, Kuzu Gulsum E, Murray Iain A, Lin Jyh-Ming, Smits Jos G A, van Vlijmen-Willems Ivonne M, Amin Shantu G, Perdew Gary H, van den Bogaard Ellen H
Department of Dermatology, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Nijmegen, the Netherlands.
Department of Veterinary and Biomedical Sciences, and Center for Molecular Toxicology and Carcinogenesis, Penn State University, University Park, PA, USA.
Biochem Pharmacol. 2023 Feb;208:115400. doi: 10.1016/j.bcp.2022.115400. Epub 2022 Dec 24.
Therapeutic aryl hydrocarbon receptor (AHR) modulating agents gained attention in dermatology as non-steroidal anti-inflammatory drugs that improve skin barrier properties. By exploiting AHR's known ligand promiscuity, we generated novel AHR modulating agents by lead optimization of a selective AHR modulator (SAhRM; SGA360). Twenty-two newly synthesized compounds were screened yielding two novel derivatives, SGA360f and SGA388, in which agonist activity led to enhanced keratinocyte terminal differentiation. SGA388 showed the highest agonist activity with potent normalization of keratinocyte hyperproliferation, restored expression of skin barrier proteins and dampening of chemokine expression by keratinocytes upon Th2-mediated inflammation in vitro. The topical application of SGA360f and SGA388 reduced acute skin inflammation in vivo by reducing cyclooxygenase levels, resulting in less neutrophilic dermal infiltrates. The minimal induction of cytochrome P450 enzyme activity, lack of cellular toxicity and mutagenicity classifies SGA360f and SGA388 as novel potential therapeutic AHR ligands and illustrates the potential of medicinal chemistry to fine-tune AHR signaling for the development of targeted therapies in dermatology and beyond.
治疗性芳烃受体（AHR）调节剂作为改善皮肤屏障特性的非甾体抗炎药在皮肤病学领域受到关注。通过利用AHR已知的配体多效性，我们通过对选择性AHR调节剂（SAhRM；SGA360）进行先导优化，生成了新型AHR调节剂。对22种新合成的化合物进行筛选，得到了两种新型衍生物SGA360f和SGA388，其激动剂活性导致角质形成细胞终末分化增强。SGA388表现出最高的激动剂活性，能有效使角质形成细胞过度增殖正常化，恢复皮肤屏障蛋白的表达，并在体外Th2介导的炎症反应中抑制角质形成细胞趋化因子的表达。局部应用SGA360f和SGA388可通过降低环氧化酶水平减轻体内急性皮肤炎症，减少嗜中性粒细胞真皮浸润。细胞色素P450酶活性的最小诱导、缺乏细胞毒性和致突变性将SGA360f和SGA388归类为新型潜在治疗性AHR配体，并说明了药物化学在微调AHR信号以开发皮肤病学及其他领域靶向治疗方面的潜力。
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