Soquelitinib (CPI-818) is a covalent, irreversible, oral and selective ITK inhibitor that preferentially inhibits Th2 cytokine production over Th1, inhibits in vivo tumor growth in mice, and decreases markers of T-cell exhaustion, resulting in an increase in tumor infiltration and up-regulation of CXCR3, IFNγ, TNFα, and CD107a expression in normal CD8 cells.

IL-2 secretion (Jurkat T cells):136 nM

In Jurkat T cells, Soquelitinib inhibits downstream TCR signaling (e.g., phosphorylation of PLCγ1 and ERK) and suppresses IL-2 secretion (IC₅₀ = 136 nM). Soquelitinib downregulates Th2 cytokines (IL-4, IL-5, IL-13) and promotes Th1 skewing. In repeatedly stimulated human CD8 T cells, 1 μM soquelitinib reduces exhaustion markers (PD1, LAG3, TIGIT, Tim3) and restores effector functions, increasing IFNγ and Granzyme B levels[1].

Oral administration of soquelitinib (30 mg/kg, b.i.d.) significantly inhibited tumor growth in multiple murine tumor models (CT26, RENCA, B16F10, EL4, A20). Soquelitinib enhanced CD8+ T-cell infiltration and cytotoxic activity (e.g., increased IFNγ, TNF, Perforin). Combined treatment with anti-PD-1 or CTLA-4 antibodies showed synergistic effects, with complete tumor regression in some cases and reduced expression of exhaustion markers in TILs. Long-term oral dosing in rats showed no observable toxicity (NOAEL >1000 mg/kg)[1].