Harnessing Glutamine-117 Plasticity toward Structure-Based Identification of Triazole IL-17 Inhibitors

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.