Discovery of a Novel Potent and Orally Efficacious PROTAC Degrader of HPK1 for Tumor Immunotherapy

Hematopoietic progenitor kinase 1 (HPK1), a negative regulator of the TCR signaling pathway, has emerged as an attractive drug target for tumor immunotherapy. Herein, we report the discovery of a series of pyrazine-based HPK1 PROTAC degraders. The representative compound 10m demonstrated potent and sustained HPK1 degradation (DC₅₀ = 5.0 ± 0.9 nM; D_max ≥ 99%). Upon TCR activation, 10m significantly inhibited SLP76 phosphorylation and enhanced ERK pathway activation through degrading HPK1, thereby stimulating IL-2 and IFN-γ release. Furthermore, 10m exhibited the ability to overcome the immunosuppressive effects imposed by PGE2, NECA or TGF-β. Notably, orally administration of 10m alone efficaciously inhibited tumor growth in an MC38 syngeneic mouse model. Moreover, 10m achieved a superior antitumor effect when combined with PD-1 blockade, suggesting the complementarity between the two treatment modalities. Overall, this work provides promising lead compounds for the clinical development of HPK1 PROTACs as small-molecule therapeutics in tumor immunotherapy.