T cells recognize antigen peptides associated with MHC (pMHC) through T cell antigen receptors (TCR). They comprise a complex of two antigen recognition subunits (TCRα/β) along with four signaling subunits (CD3γ/δ/ε/ζ). Nck is an adaptor protein. It contains three tandem Src homology 3 (SH3) domains (SH3.1, SH3.2, and SH3.3) and a C-terminal SH2 domain. Furthermore, Nck universally coordinates signaling networks critical for actin cytoskeleton organization, cell movement, or axon guidance, connecting transmembrane receptors to multiple intracellular signaling pathways. In T cells, TCR triggering is followed by direct recruitment of Nck via its N-terminal SH3 (SH3.1) domain to a proline-rich sequence (PRS) in the cytoplasmic tail of CD3ε. In this study, the authors aim to develop an immunotherapy strategy for Ads. It modulates TCR activation using a new small chemical inhibitor of the Nck-CD3ε interaction. In this study, AX-024 is an orally available, first-in-class inhibitor of the TCR-Nck interaction.
AX-024 is an orally available, first-in-class inhibitor of the TCR-Nck interaction that selectively inhibits TCR-triggered T cell activation.
AX-024 selectively inhibits TCR-triggered T cell activation with an IC50 ~1 nM and specifically targets the Nck-CD3ε interaction. Meanwhile, it specifically inhibits the earliest TCR signaling events.
AX-024 attenuates the severity of skin inflammation in a psoriasis model as well as of lung inflammation in an asthma model. Oral administration of AX-024 prevents the development of neurological symptoms in a model of multiple sclerosis. Meanwhile, it exerts a long-lasting therapeutic effect in the experimental autoimmune encephalitis (EAE) model of multiple sclerosis (MS). AX-024 inhibits effector TH cell differentiation toward proinflammatory subsets. Besides, it allows the harnessing of an efficient memory T cell response against a mouse pathogen.
In summary, AX-024 modulates cell signaling by targeting SH3 domains and in turn is a first-in-class inhibitor of TCR signals. Furthermore, the low-acute toxicity profile of AX-024 and its high potency and selectivity, together with the fact that it targets TCR signals, make AX-024 a candidate for evaluation as an oral drug in clinical trials of psoriasis, MS, and, presumably, many other ADs.
Borroto A, et al. Sci Transl Med. 2016 Dec 21;8(370):370ra184.