Highly selective HPK1 inhibitor NDI-101150 mediates immune cell activation and robust antitumor responses, distinct from immune checkpoint blockade.

ABSTRACT:

Background

HPK1 (hematopoietic progenitor kinase 1, MAP4K1), an MAP4K serine/threonine kinase family member, is a negative regulator of immune cell function. Genetic HPK1 kinase inactivation or knockout in mice leads to immune cell activation and tumor growth suppression, providing a strong rationale for targeting HPK1 kinase activity as an immuno-oncology therapy.

Methods

A structure-guided drug design approach was used to identify a highly potent and selective small molecule inhibitor of HPK1 kinase activity, NDI-101150. The effect of NDI-101150 in vitro was evaluated on multiple immune cell types and in multiple syngeneic tumor models in vivo.

Results

Treatment with NDI-101150 enhanced T-cell activation in immune-suppressive or exhausted conditions, augmented B-cel

SUBMITTER: Ciccone DN 

PROVIDER: S-EPMC12599120 | biostudies-literature | 2025 Jul

REPOSITORIES: biostudies-literature