Discovery of Novel PROTAC-Based HPK1 Degraders with High Potency and Selectivity for Cancer Immunotherapy

Hematopoietic progenitor kinase 1 (HPK1, MAP4K1), a serine/threonine (SER/THR) kinase, has been identified as a negative immune regulator of T-cell receptor signaling. Deprivation of the HPK1 function suppresses tumor growth, providing an attractive strategy for cancer immunotherapy. Herein, we present a novel PROTAC-based HPK1 degrader compound <b>DD205-291</b> with high selectivity and potency. <b>DD205-291</b> showed a dose-dependent inhibition of SLP-76 phosphorylation and an induction of IL-2 and IFN-γ. Compared with other inhibitors, <b>DD205-291</b> exhibited good efficacy and a favorable safety profile in the MC38 model. Specifically, oral administration of <b>DD205-291</b> at 0.5 mg/kg in combination with anti-PD1 resulted in significant suppression with a TGI value of 91.0%. Furthermore, <b>DD205-291</b> exhibited a low risk of cardiotoxicity and a wide safety window. This research effort demonstrates that <b>DD205-291</b> is a promising preclinical candidate (PCC) for potential mono- and comboimmunotherapy of cancer.