Identification of Novel HPK1 Hit Inhibitors: From In Silico Design to In Vitro Validation.

ABSTRACT: Hematopoietic progenitor kinase 1 (HPK1), a negative regulator of T-cells, B-cells, and dendritic cells, has gained attention in antitumor immunotherapy research over the past decade. No HPK1 inhibitor has yet reached clinical approval, largely due to selectivity and drug-like limitations. Leveraging the available structural insights into HPK1, we conducted a rational hit identification using a structure-based virtual screening of over 600,000 drug-like molecules from ASINEX and OTAVA databases. A series of molecular docking studies, in vitro kinase assays, and molecular dynamics simulations were conducted to identify viable HPK1 inhibitor hits. This approach resulted in two promising novel hit scaffolds, 4H-Pyrido[1,2-a] thieno[2,3-d] pyrimidin-4-one (ISR-05) and quinolin-2(1H)-one (ISR-0

SUBMITTER: Isawi IH 

PROVIDER: S-EPMC12072202 | biostudies-literature | 2025 May

REPOSITORIES: biostudies-literature