Current strategies for targeting HPK1 in cancer and the barriers to preclinical progress.

INTRODUCTION: Hematopoietic progenitor kinase 1 (HPK1), a 97-kDa serine/threonine Ste20-related protein kinase, functions as an intracellular negative regulator, primarily in hematopoietic lineage cells, where it regulates T cells, B cells, dendritic cells and other immune cells. Loss of HPK1 kinase activity results in exacerbated cytokine secretion, enhanced T cell signaling, improved viral clearance, and thus increased restraint of tumor growth. These findings highlight HPK1 as a promising target for immuno-oncology treatments, culminating in the advancement of candidate compounds targeting HPK1 to clinical trials by several biotech enterprises.

AREAS COVERED: Through searching PubMed, Espacenet-patent search, and clinicaltrials.gov, this review provides a comprehensive analysis of HPK1, encompassing its structure and roles in various downstream signaling pathways, the consequences of constitutive activation of HPK1, and potential therapeutic strategies to treat HPK1-driven malignancies. Moreover, the review outlines the patents issued for small molecule inhibitors and clinical investigations of HPK1.

EXPERT OPINION: To enhance the success of tumor immunotherapy in clinical trials, it is important to develop protein degraders, allosteric inhibitors, and antibody-drug conjugates based on the crystal structure of HPK1, and to explore combination therapy approaches. Although several challenges remain, development of HPK1 inhibitors display promising in preclinical and clinical studies.