Discovery and Structural Optimization of Covalent ZAP-70 Kinase Inhibitors against Psoriasis

Area of Science:

• Immunology
• Dermatology
• Medicinal Chemistry

Background:

• Psoriasis is a T cell-mediated chronic inflammatory skin disease with unmet therapeutic needs.
• Zeta-chain-associated protein kinase 70 kDa (ZAP-70) is a key mediator in T cell receptor signaling and a potential therapeutic target for autoimmune diseases.

Purpose of the Study:

• To structurally optimize covalent ZAP-70 inhibitors for enhanced potency and selectivity.
• To evaluate the therapeutic potential of optimized inhibitors, specifically compound 25 (RDN2150), in preclinical models of psoriasis.

Main Methods:

• Structure-based drug design and medicinal chemistry efforts were employed for inhibitor optimization.
• In vitro assays assessed ZAP-70 inhibition, selectivity, T cell activation, and cytokine production.
• Topical application of compound 25 was evaluated in an imiquimod-induced psoriasis mouse model.

Main Results:

• Compound 25 (RDN2150) demonstrated potent and selective inhibition of ZAP-70.
• It effectively suppressed T cell activation and the production of inflammatory cytokines.
• Topical administration of compound 25 showed significant efficacy in a preclinical psoriasis model.

Conclusions:

• Structural optimization led to the discovery of compound 25 (RDN2150), a potent ZAP-70 inhibitor.
• Compound 25 exhibits promising anti-inflammatory and anti-psoriatic effects.
• Targeting ZAP-70 represents a viable therapeutic strategy for psoriasis management.