7AMA

IL-17A in complex with small molecule modulators

Summary for 7AMA

• Entry DOI: 10.2210/pdb7ama/pdb
• Descriptor: Interleukin-17A, ~{N}-[(2~{S})-1,1-dicyclopropyl-3-[[4-(3,5-dimethyl-1~{H}-pyrazol-4-yl)phenyl]amino]-3-oxidanylidene-propan-2-yl]-2-propan-2-yl-pyrazole-3-carboxamide (3 entities in total)
• Functional Keywords: interleukin il-17a inhibitor receptor, immune system
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 25789.28

Authors

Hakansson, M.,Kimbung, R.,Logan, D.,Walse, U.B.,de Groot, M.J.,Andrews, M.D.,Dack, K.N.,Lambert, M. (deposition date: 2020-10-08, release date: 2022-04-20, Last modification date: 2024-10-23)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.48 Å)