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

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

Research output: Contribution to journal › Article › peer-review

3 Scopus citations

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.

Original language	English (US)
Article number	115400
Journal	Biochemical Pharmacology
Volume	208
DOIs	https://doi.org/10.1016/j.bcp.2022.115400
State	Published - Feb 2023

All Science Journal Classification (ASJC) codes

Biochemistry
Pharmacology

Access to Document

10.1016/j.bcp.2022.115400

Cite this

Rikken, G., Smith, K. J., van den Brink, N. J. M., Smits, J. P. H., Gowda, K., Alnemri, A., Kuzu, G. E., Murray, I. A., Lin, J. M., Smits, J. G. A., van Vlijmen-Willems, I. M., Amin, S. G., Perdew, G. H., & van den Bogaard, E. H. (2023). Lead optimization of aryl hydrocarbon receptor ligands for treatment of inflammatory skin disorders. Biochemical Pharmacology, 208, Article 115400. https://doi.org/10.1016/j.bcp.2022.115400

@article{11a90ad17f06480f967c5396e4e9e0c1,

title = "Lead optimization of aryl hydrocarbon receptor ligands for treatment of inflammatory skin disorders",

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.",

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

note = "Publisher Copyright: {\textcopyright} 2023 The Authors",

year = "2023",

month = feb,

doi = "10.1016/j.bcp.2022.115400",

language = "English (US)",

volume = "208",

journal = "Biochemical Pharmacology",

issn = "0006-2952",

publisher = "Elsevier Inc.",

}

Rikken, G, Smith, KJ, van den Brink, NJM, Smits, JPH, Gowda, K, Alnemri, A, Kuzu, GE, Murray, IA , Lin, JM, Smits, JGA, van Vlijmen-Willems, IM, Amin, SG, Perdew, GH & van den Bogaard, EH 2023, 'Lead optimization of aryl hydrocarbon receptor ligands for treatment of inflammatory skin disorders', Biochemical Pharmacology, vol. 208, 115400. https://doi.org/10.1016/j.bcp.2022.115400

TY - JOUR

T1 - Lead optimization of aryl hydrocarbon receptor ligands for treatment of inflammatory skin disorders

AU - Rikken, Gijs

AU - Smith, Kayla J.

AU - van den Brink, Noa J.M.

AU - Smits, Jos P.H.

AU - Gowda, Krishne

AU - Alnemri, Angela

AU - Kuzu, Gulsum E.

AU - Murray, Iain A.

AU - Lin, Jyh Ming

AU - Smits, Jos G.A.

AU - van Vlijmen-Willems, Ivonne M.

AU - Amin, Shantu G.

AU - Perdew, Gary H.

AU - van den Bogaard, Ellen H.

PY - 2023/2

Y1 - 2023/2

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85145992664&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85145992664&partnerID=8YFLogxK

U2 - 10.1016/j.bcp.2022.115400

DO - 10.1016/j.bcp.2022.115400

M3 - Article

C2 - 36574884

AN - SCOPUS:85145992664

SN - 0006-2952

VL - 208

JO - Biochemical Pharmacology

JF - Biochemical Pharmacology

M1 - 115400

ER -

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

Abstract

All Science Journal Classification (ASJC) codes

Access to Document

Other files and links

Fingerprint

Cite this