AX-024 is a novel chemical compound that acts as an orally available inhibitor of the TCR-Nck interaction. Its primary mechanism of action is the selective inhibition of T cell activation triggered by TCR stimulation. With an IC50 value of approximately 1 nM, AX-024 effectively modulates cell signaling by specifically targeting SH3 domains. Additionally, AX-024 demonstrates desirable characteristics such as low acute toxicity, high potency, and excellent selectivity. Notably, it exhibits strong inhibitory effects on the production of IL-6, TNF-α, IFN-γ, IL-10, and IL-17A.

AX-024 demonstrates exceptional efficacy, being over 10,000 times more effective than the earlier compound AX-000 in inhibiting T-cell proliferation prompted by T-cell receptor (TCR) activation, with an IC50 of 1 nM and observable inhibitory actions at concentrations as low as 1 pM. Furthermore, it significantly suppresses cytokine release from human peripheral blood mononuclear cells, including interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), IL-10, and IL-17A, at 10 nM concentration when stimulated with anti-CD3, outperforming AX-000 in efficiency. In the specific context of CD8+ T cells from OT1 TCR transgenic (OT1 Tg) mice, AX-024 drastically reduces T cell proliferation at just 0.1 nM in cells with a wild-type (WT) PRS mutation. Coimmunoprecipitation assays reveal that, while Nck typically associates with the TCR following activation, this interaction is dose-dependently obstructed by AX-024 starting at 1 nM concentrations, highlighting its potent inhibitory mechanism [1].

The AX-024-treated group exhibited fewer scales and a reduction in skin thickening compared to the vehicle group. It significantly lessened the thickening of skin layers, particularly the dermis, closely mirroring the effects seen in mice treated with a control cream without imiquimod (IMQ). Moreover, AX-024 notably decreased the presence of airway inflammatory cells in both assays. Additionally, mice administered AX-024 showed rapid recovery from neurological impairments and weight loss, achieving a symptom-free state by day 30—a stark contrast to mice receiving the vehicle, which continued to exhibit ataxia and a loss of the righting reflex [1].