The development of small-molecule inhibitors targeting HPK1.

Hematopoietic progenitor kinase 1 (HPK1), a 97-kDa serine/threonine Ste20-related protein kinase, is a negative regulator of T cells, B cells, and dendritic cells-mediated immune responses and is primarily expressed in hematopoietic lineage cells. HPK1 regulates different cellular processes by interacting with a variety of substrates and adaptors, including immune cell activation, cellular differentiation, proliferation, adhesion, and apoptosis. In HPK1 mice, T cells over-proliferate in response to stimulation by anti-CD3 and anti-CD28 antibodies, and these cells can secrete more proinflammatory cytokines to enhance T-cell activation and tumor growth inhibition when immunized with T cell-dependent antigens. Therefore, HPK1 may be associated with occurrence and development of human malignant tumors and is an effective antitumor immunotherapy target. In this perspective review, the biological rationale and potential of HPK1 as a promising candidate target for cancer immunotherapies and the latest research progress of HPK1 are summarized, with special emphasis on the current small-molecule inhibitors of HPK1 in preclinical and clinical studies.