An updated review of small-molecule HPK1 kinase inhibitors (2016-present).

Hematopoietic progenitor kinase 1 (HPK1) is a serine-threonine kinase specific to hematopoiesis and a member of the MAP4K family of Ste20-related protein kinases. Targeting HPK1 to ameliorate T cell exhaustion and enhance T cell functions is a promising strategy for clinical immunotherapies. Numerous studies have reported the progress in developing effective HPK1 inhibitors and elucidating their mechanisms of action. However, most inhibitors affect multiple signaling pathways, resulting in unintended side effects that limit their clinical development and application. Herein, we reviewed HPK1-related signaling pathways, clinical candidates and recent advances in small-molecule inhibitors targeting HPK1. Additionally, we present our perspectives on current challenges and potential future research field, hoping to provide inspiration for the development of novel HPK1 inhibitors.