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

Area of Science:

• Medicinal Chemistry
• Immunology
• Drug Discovery

Background:

• Interleukin-17 (IL-17) is a pro-inflammatory cytokine vital for host defense but implicated in autoimmune diseases.
• Current antibody-based IL-17 inhibitors show clinical success but oral small molecule alternatives are needed.
• Previous small molecule IL-17 inhibitors faced challenges in preclinical and clinical development.

Purpose of the Study:

• To discover novel, orally bioavailable small molecule inhibitors targeting IL-17.
• To identify new chemical scaffolds that can effectively bind to the IL-17 target.
• To overcome limitations of existing IL-17 inhibitor development.

Main Methods:

• Employed a structure-based library approach utilizing a 1,2,4-triazole scaffold.
• Designed novel motifs to interact with the Trp90 pocket, a key IL-17 binding site.
• Utilized X-ray crystallography to guide optimization of potent inhibitor candidates.

Main Results:

• Identified a 1,2,4-triazole scaffold acting as an effective amide bioisostere.
• Developed structurally diverse motifs targeting the Trp90 pocket with high plasticity.
• Achieved low nanomolar cellular activity with optimized triazole-based IL-17 inhibitors.

Conclusions:

• The discovered 1,2,4-triazole-based compounds are promising lead candidates for developing new IL-17 inhibitors.
• This scaffold offers a viable alternative to antibody therapies for IL-17 mediated diseases.
• Further development could lead to orally available treatments for inflammatory and autoimmune conditions.