7AMG

IL-17A in complex with small molecule modulators

7AMG の概要

• エントリーDOI: 10.2210/pdb7amg/pdb
• 関連するPDBエントリー: 7AMA
• 分子名称: Interleukin-17A, (3~{R})-4-[4-[[(2~{S})-2-[[2,2-bis(fluoranyl)-2-phenyl-ethanoyl]amino]-3-(2-chlorophenyl)propanoyl]amino]phenyl]-3-[[(2~{S})-3-methyl-2-[2-[2-[(2-methylpropan-2-yl)oxycarbonylamino]ethoxy]ethanoylamino]butanoyl]amino]butanoic acid (3 entities in total)
• 機能のキーワード: interleukin il-17a inhibitor receptor, immune system
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 52289.99

構造登録者

Hakansson, M.,Kimbung, R.,Logan, D.,Walse, U.B.,de Groot, M.J.,Andrews, M.D.,Dack, K.N.,Lambert, M. (登録日: 2020-10-08, 公開日: 2022-04-20, 最終更新日: 2024-10-16)

主引用文献

Andrews, M.D.,Dack, K.N.,de Groot, M.J.,Lambert, M.,Sennbro, C.J.,Larsen, M.,Stahlhut, M.
Discovery of an Oral, Rule of 5 Compliant, Interleukin 17A Protein-Protein Interaction Modulator for the Potential Treatment of Psoriasis and Other Inflammatory Diseases.
J.Med.Chem., 65:8828-8842, 2022

PubMed Abstract: Interleukin 17A (IL-17A) is an interleukin cytokine whose dysregulation is implicated in autoimmune disorders such as psoriasis, and monoclonal antibodies against the IL-17A pathway are now well-established and very effective treatments. This article outlines the work that led to the identification of as an oral, small-molecule protein-protein interaction modulator (PPIm) clinical development candidate. Protein crystallography provided knowledge of the key binding interactions between small-molecule ligands and the IL-17A dimer, and this helped in the multiparameter optimization toward identifying an orally bioavailable, Rule of 5 compliant PPIm of IL-17A. Overlap of early ligands led to a series of benzhydrylglycine-containing compounds that allowed the identification of dimethylpyrazole as a key substituent that gave PPIm with oral bioavailability. Exploration of the amino acid portion of the structure then led to dicyclopropylalanine as a group that gave potent and metabolically stable compounds, including the development candidate .

PubMed: 35767390
DOI: 10.1021/acs.jmedchem.2c00422

実験手法

X-RAY DIFFRACTION (3.18 Å)