9fl3 | pdb_00009fl3
Crystal structure of IL-17A in complex with compound 26
Structural highlights
FunctionIL17_HUMAN Induces stromal cells to produce proinflammatory and hematopoietic cytokines. Enhances the surface expression of ICAM1/intracellular adhesion molecule 1 in fibroblasts. Publication Abstract from PubMedIL-17, a pro-inflammatory cytokine produced mainly by Th17 cells, is involved in the immune response to fungal and bacterial infections, whereas its aberrant production is associated with autoimmune and inflammatory diseases. IL-17 blocking antibodies like secukinumab (Cosentyx) have been developed and are used to treat conditions like psoriasis, psoriatic arthritis, and ankylosing spondylitis. Recently, the low molecular weight IL-17 inhibitor LY3509754 entered the clinic but was discontinued in Phase 1 due to adverse effects. In this study, we explored the replacements of furazan moiety posing a potential toxicology risk in LY3509754. By exploring replacements such as heterocycles as amide-isosteres as well as alpha-F-acrylamides, two compounds (18 and 26) were identified. Both compounds effectively reduced knee swelling in a rat arthritis model. However, early rat and dog toxicity studies revealed adverse findings, preventing their further development and indicating that furazan might not be responsible for the adverse effects of LY3509754. Discovery and In Vivo Exploration of 1,3,4-Oxadiazole and alpha-Fluoroacrylate Containing IL-17 Inhibitors.,Velcicky J, Bauer MR, Schlapbach A, Lapointe G, Meyer A, Vogtle M, Blum E, Ngo E, Rolando C, Nimsgern P, Teixeira-Fouchard S, Lehmann H, Furet P, Berst F, Schumann J, Stringer R, Larger P, Schmid C, Prendergast CT, Riek S, Schmutz P, Lehmann S, Berghausen J, Scheufler C, Rondeau JM, Burkhart C, Knoepfel T, Gommermann N J Med Chem. 2024 Sep 26;67(18):16692-16711. doi: 10.1021/acs.jmedchem.4c01520. , Epub 2024 Sep 14. PMID:39276085[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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