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Publication Abstract from PubMed

The proinflammatory cytokine IL-17 is crucial for host defense but has also been linked to various inflammatory and autoimmune diseases. Antibody-based IL-17 inhibitors like secukinumab (Cosentyx) have demonstrated clinical success in psoriasis, psoriatic arthritis, and ankylosing spondylitis, sparking efforts to develop orally bioavailable small molecule alternatives. However, most small molecule IL-17 inhibitors failed in preclinical and clinical stages due to safety concerns and other challenges. This work describes the discovery of a 1,2,4-triazole scaffold that acts as an amide bioisostere. Its unique vector toward the Trp90 pocket, a key cavity for ligand binding, required the development of novel motifs. A structure-based library approach, considering the high plasticity of the Gln117 side chain, yielded structurally diverse Trp90 pocket binding motifs. The X-ray structures of the most potent hits guided subsequent optimization, resulting in triazole-based IL-17 inhibitors with low nanomolar cellular activity, which are promising leads for further development.

Harnessing Glutamine-117 Plasticity toward Structure-Based Identification of Triazole IL-17 Inhibitors.,Bauer MR, Velcicky J, Goetz A, Furet P, Nimsgern P, Tichkule R, Schlapbach A, Meyer A, Vogtle M, Rolando C, Lehmann H, Berst F, Riek S, Schmutz P, Lehmann S, Scheufler C, Rondeau JM, Burkhart C, Gommermann N, Knoepfel T J Med Chem. 2025 Dec 7. doi: 10.1021/acs.jmedchem.5c02794. PMID:41355177^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.