Bauer, Matthias-1, Velcicky, Juraj, Gommermann, Nina and Knoepfel, Thomas (2025) Harnessing glutamine-117 plasticity toward structure-based identification of triazole IL-17 inhibitors. Journal of medicinal chemistry, 68 (24). pp. 26494-26512. ISSN 1520-4804

Abstract

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.

Item Type:	Article
Keywords:	IL-17, triazoles, LMW, modeling
Date Deposited:	17 Jan 2026 00:46
Last Modified:	17 Jan 2026 00:46
URI:	https://oak.novartis.com/id/eprint/58650