化学性质：                                                                                                             

产品描述：                                                                                                             

AX-024 is an cytokine release inhibitor which can strongly inhibit the production of interleukin-6 (IL-6), tumor necrosis factor-α (TNFα), interferon-γ (IFN-γ), IL-10 and IL-17A. IL-6, TNFα, IFN-γ, IL-10 and IL-17A[1]

Compound AX-024 is >10,000-fold more potent than the AX-000 hit in terms of inhibition of TCR-triggered T cell proliferation. The IC50 of AX-024 in this assay is 1 nM, although it shows inhibitory effects at a concentration of 1 pM or less. AX-024 is also a much more potent inhibitor of cytokine release by human peripheral blood mononuclear cells stimulated with anti-CD3 than AX-000, strongly hindering interleukin-6 (IL-6), tumor necrosis factor-α (TNFα), interferon-γ (IFN-γ), IL-10, and IL-17A production at a concentration of 10 nM. In CD8+ T cells of OT1 TCR transgenic (OT1Tg) mice bearing wild-type (WT) AX-024 strongly inhibits T cell proliferation at a concentration of 0.1 nM when OT1Tg T cells are WT for the PRS mutation. Coimmunoprecipitation experiments in these cells show that Nck recruitment to the TCR is induced upon stimulation in the absence of drug but is inhibited in the presence of AX-024 in a dose-dependent manner at concentrations starting from 1 nM[1].

The AX-024-treated group presents less scales and reduces skin thickening compare to the vehicle group. Treatment with AX-024 significantly reduces thickening of both skin layers, but more effectively of the dermis, which rather resembles that of mice treated with a control cream lacking imiquimod (IMQ). Treatment with AX-024 significantly diminishes the number of airway inflammatory cells in both assays. Mice receiving AX-024 rapidly recovers from neurological impairment and weight loss, becoming symptom-free by day 30, unlike mice that receives the vehicle, in which ataxia and loss of the righting reflex persist[1].

[1]. Borroto A, et al. First-in-class inhibitor of the T cell receptor for the treatment of autoimmune diseases. Sci Transl Med. 2016 Dec 21;8(370):370ra184.

特别提醒：