Lead optimization of aryl hydrocarbon receptor ligands for treatment of inflammatory skin disorders

Gijs Rikken; Kayla J Smith; Noa J M van den Brink; Jos P H Smits; Krishne Gowda; Angela Alnemri; Gulsum E Kuzu; Iain A Murray; Jyh-Ming Lin; Jos G A Smits; Ivonne M van Vlijmen-Willems; Shantu G Amin; Gary H Perdew; Ellen H van den Bogaard

doi:10.1016/j.bcp.2022.115400

Lead optimization of aryl hydrocarbon receptor ligands for treatment of inflammatory skin disorders

Biochem Pharmacol. 2023 Feb:208:115400. doi: 10.1016/j.bcp.2022.115400. Epub 2022 Dec 24.

Affiliations

¹ Department of Dermatology, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Nijmegen, the Netherlands.
² Department of Veterinary and Biomedical Sciences, and Center for Molecular Toxicology and Carcinogenesis, Penn State University, University Park, PA, USA.
³ Department of Pharmacology, Penn State College of Medicine, Department of Biochemistry and Molecular Biology, Penn State College of Medicine, Hershey, PA, USA.
⁴ Metabolomics Facility, The Huck Institutes of the Life Sciences, The Pennsylvania State University, University Park, PA, USA.
⁵ Department of Molecular Developmental Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences, Radboud University, Nijmegen, the Netherlands.
⁶ Department of Veterinary and Biomedical Sciences, and Center for Molecular Toxicology and Carcinogenesis, Penn State University, University Park, PA, USA. Electronic address: [email protected].
⁷ Department of Dermatology, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Nijmegen, the Netherlands. Electronic address: [email protected].

PMID: 36574884
DOI: 10.1016/j.bcp.2022.115400

Abstract

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Humans
Inflammation / metabolism
Keratinocytes / metabolism
Ligands
Receptors, Aryl Hydrocarbon* / metabolism
Skin / metabolism
Skin Diseases* / drug therapy

Substances

Receptors, Aryl Hydrocarbon
Ligands