Small Molecule IL-36γ Antagonist as a Novel Therapeutic Approach for Plaque Psoriasis.

Autor: Todorović V; AbbVie Inc., 1 North Waukegan Rd., North Chicago, IL, 60064, USA. Viktor.Todorovic@abbvie.com., Su Z; AbbVie Inc., 1 North Waukegan Rd., North Chicago, IL, 60064, USA., Putman CB; AbbVie Inc., 1 North Waukegan Rd., North Chicago, IL, 60064, USA., Kakavas SJ; AbbVie Inc., 1 North Waukegan Rd., North Chicago, IL, 60064, USA., Salte KM; AbbVie Inc., 1 North Waukegan Rd., North Chicago, IL, 60064, USA., McDonald HA; AbbVie Inc., 1 North Waukegan Rd., North Chicago, IL, 60064, USA., Wetter JB; AbbVie Inc., 1 North Waukegan Rd., North Chicago, IL, 60064, USA., Paulsboe SE; AbbVie Inc., 1 North Waukegan Rd., North Chicago, IL, 60064, USA., Sun Q; AbbVie Inc., 1 North Waukegan Rd., North Chicago, IL, 60064, USA., Gerstein CE; AbbVie Inc., 1 North Waukegan Rd., North Chicago, IL, 60064, USA., Medina L; AbbVie Bioresearch Center, 381 Plantation St., Worcester, MA, 01605, USA., Sielaff B; AbbVie Bioresearch Center, 381 Plantation St., Worcester, MA, 01605, USA., Sadhukhan R; AbbVie Bioresearch Center, 381 Plantation St., Worcester, MA, 01605, USA., Stockmann H; AbbVie Inc., 1 North Waukegan Rd., North Chicago, IL, 60064, USA., Richardson PL; AbbVie Inc., 1 North Waukegan Rd., North Chicago, IL, 60064, USA., Qiu W; AbbVie Inc., 1 North Waukegan Rd., North Chicago, IL, 60064, USA., Argiriadi MA; AbbVie Bioresearch Center, 381 Plantation St., Worcester, MA, 01605, USA., Henry RF; AbbVie Inc., 1 North Waukegan Rd., North Chicago, IL, 60064, USA., Herold JM; AbbVie Bioresearch Center, 381 Plantation St., Worcester, MA, 01605, USA., Shotwell JB; AbbVie Inc., 1 North Waukegan Rd., North Chicago, IL, 60064, USA., McGaraughty SP; AbbVie Inc., 1 North Waukegan Rd., North Chicago, IL, 60064, USA., Honore P; AbbVie Inc., 1 North Waukegan Rd., North Chicago, IL, 60064, USA., Gopalakrishnan SM; AbbVie Inc., 1 North Waukegan Rd., North Chicago, IL, 60064, USA., Sun CC; AbbVie Inc., 1 North Waukegan Rd., North Chicago, IL, 60064, USA., Scott VE; AbbVie Inc., 1 North Waukegan Rd., North Chicago, IL, 60064, USA. Victoria.E.Scott@abbvie.com.
Jazyk: angličtina
Zdroj: Scientific reports [Sci Rep] 2019 Jun 24; Vol. 9 (1), pp. 9089. Date of Electronic Publication: 2019 Jun 24.
DOI: 10.1038/s41598-019-45626-w
Abstrakt: 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.
Databáze: MEDLINE
Externí odkaz:
Nepřihlášeným uživatelům se plný text nezobrazuje