Small Molecule ITK and Pan-TRK Kinase Inhibitor (PF-07245303) for the Potential Topical Treatment of Atopic Dermatitis
Atopic dermatitis (AD) is a chronic inflammatory skin disease driven by cytokines interleukin-4 (IL-4) and interleukin-13 (IL-13) and associated with skin barrier disruption and pruritis. Interleukin-2-inducible T cell kinase (ITK) is a tyrosine kinase expressed by T cells which functions to amplify T cell receptor (TCR)-dependent signals, and ITK deletion or kinase inhibition reduces TCR-induced IL-4 and IL-13 production. Nerve growth factor (NGF) is a neurotrophic factor which signals via the receptor tropomyosin-related kinase A (TRKA) and can promote pruritis in the skin.  The expression of both NGF and TRKA are enhanced in atopic dermatitis skin lesions, and levels of NGF in AD skin lesions correlated with itch severity. Here we describe a compound, PF-07245303, which potently inhibits ITK and TRK kinases (TRKA, B, and C). This compound demonstrated inhibition of TCR-induced, ITK-dependent phosphorylation of PLC?1 and potently inhibits TCR stimulated IL-2 production from purified human T cells. Moreover, this ITK/TRK kinase inhibitor suppressed production of inflammatory cytokines from Th1, Th2, Th17, and CD8 T cells. In biochemical and cell-based assays PF-07245303 inhibited receptor kinases TRKA, TRKB, and TRKC and suppressed NGF-induced human basophil activation.  Using a human skin explant model of atopic dermatitis, PF-07245303 demonstrated pharmacological activity by inhibiting phosphorylation of TRKA and suppressed expression of cytokines from TCR-activated resident dermal T cells. These results suggest that dual inhibition of ITK and TRKs with PF-07245303 suppress(es) dermal T cell activation and NGF-dependent responses which contribute to atopic dermatitis. Overall design: Skin explants were stimulated with CD3/CD28/TH2 cytokine cocktail and a ITK/TRK inhibitor