Abstract
IL-36 cytokines are pro-inflammatory members of the IL-1 family that are upregulated in inflammatory disorders. Specifically, IL-36γ is highly expressed in active psoriatic lesions and can drive pro-inflammatory processes in 3D human skin equivalents supporting a role for this target in skin inflammation. Small molecule antagonists of interleukins have been historically challenging to generate. Nevertheless, we performed a small molecule high-throughput screen to identify IL-36 antagonists using a novel TR-FRET binding assay. Several compounds, including 2-oxypyrimidine containing structural analogs of the marketed endothelin receptor A antagonist Ambrisentan, were identified as hits from the screen. A-552 was identified as a the most potent antagonist of human IL-36γ, but not the closely related family member IL-36α, was capable of attenuating IL-36γ induced responses in mouse and human disease models. Additionally, x-ray crystallography studies identified key amino acid residues in the binding pocket present in human IL-36γ that are absent in human IL-36α. A-552 represents a first-in-class small molecule antagonist of IL-36 signaling that could be used as a chemical tool to further investigate the role of this pathway in inflammatory skin diseases such as psoriasis.
Highlights
Plaque psoriasis or psoriasis vulgaris (PV) is a chronic inflammatory skin disease whose initiation is not well understood but is mechanistically driven by the IL-17/IL-23 axis leading to keratinocyte hyper proliferation and resultant acanthosis, formation of characteristic rete ridges in the epidermis and significant immune cell infiltration into the dermis[1,2]
Binding of IL-36 agonists to IL-36 receptor subunit (IL-36R)/IL-1RAcP heterodimer induces signaling through MyD88/IRAK complex leading to the activation of NF-κB and MAPKs signaling cascades shared among IL-1R superfamily members[4,5]
Recent studies have shown that chronic administration of mouse IL-36α into mouse ear skin leads to a thickening of the ear, epidermal hyperplasia, significant immune cell infiltration and dysregulation of key psoriasis relevant target genes that can be attenuated by pretreatment with an antagonistic mouse IL-36R antibody supportive of a direct role for IL-36 signaling in driving skin inflammation in mice[15]
Summary
Plaque psoriasis or psoriasis vulgaris (PV) is a chronic inflammatory skin disease whose initiation is not well understood but is mechanistically driven by the IL-17/IL-23 axis leading to keratinocyte hyper proliferation and resultant acanthosis, formation of characteristic rete ridges in the epidermis and significant immune cell infiltration into the dermis[1,2]. Recent studies have shown that chronic administration of mouse IL-36α into mouse ear skin leads to a thickening of the ear, epidermal hyperplasia, significant immune cell infiltration and dysregulation of key psoriasis relevant target genes that can be attenuated by pretreatment with an antagonistic mouse IL-36R antibody supportive of a direct role for IL-36 signaling in driving skin inflammation in mice[15]. A-552 attenuated human IL-36γ induced pro-inflammatory responses in preclinical models This is the first report of the identification of small molecule antagonists for the IL-36R/IL-36γ complex that are active in models of skin inflammation and provides the opportunity to target inhibition of this signaling pathway for treatment of multiple inflammatory indications
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