Hematopoietic progenitor kinase-1 (HPK1) is a serine/threonine Ste20 related protein kinase. It expresses only in hematopoietic cells (such as T cells, B cells, and dendritic cells). Specifically, HPK1 is a negative feedback regulator of T cell receptor signaling and can inhibit T cell proliferation and effector function. In addition, the enhancement of antigen-specific T cell immunity has shown significant therapeutic benefits in infectious diseases and cancer. Besides, HPK1 plays the role of enzyme and scaffold. Inhibitors of chemical HPK1 kinase function may enhance T cells and enhance anti-tumor immunity. Furthermore, HPK1 is a tumor suppressor that targets AXL for degradation via the endocytic pathway. Meanwhile, HPK1 loss of function may contribute to AXL overexpression and thereby enhance AXL-dependent downstream signaling and tumor invasion in PDAC. Nonetheless, HPK1/MAP4K1 has inhibition effects in T-cell activation and the promoting effects of GLK on tumorigenesis. GNE-1858 is a potent and ATP-competitive HPK1 inhibitor.

But, how does GNE-1858 has anti-inflammatory activity via HPK1? Let’s discuss it in detail. In the beginning, GNE-1858 is a potent and ATP-competitive HPK1 inhibitor. GNE-1858 binds to the active site and inhibits SPL76 Phosphorylation. Interestingly,  GNE-1858 potently inhibits all three HPK1 kinase domain variants under investigation in a dose-dependent manner. Importantly, the potencies against wild-type and the active mimetic mutants are identical with an IC₅₀ value of 1.9 nM in the SLP76 phosphorylation assay. Additionally, GNE-1858 also inhibited the residual kinase activity of HPK1-SA at 4.5 nM. In addition, HPK1 forms reversible dimers in solution. To our delight, GNE-1858 is a potent and ATP-competitive HPK1 inhibitor.

References:

Wu P, et al. Structure. 2019 Jan 2;27(1):125-133.e4.