Discovery of HDM2004, a potent, selective and orally bioavailable HPK1 inhibitor for tumor immunotherapy.

Hematopoietic progenitor kinase 1 (HPK1) has emerged as a compelling target for tumor immunotherapy due to its pivotal role in regulating key cellular processes, including survival, migration, apoptosis, and autophagy. In this comprehensive study, we characterized the pharmacological profile of a novel HPK1 inhibitor HDM2004 (compound 37). Through systematic structure-activity relationship (SAR) optimization, HDM2004 was identified as a highly potent HPK1 inhibitor (IC50 = 1.89 nM) with >30-fold selectivity over the closely related kinase GLK. The compound exhibits favorable drug-like properties, including high metabolic stability (human liver microsomal half-life >300 min) and minimal inhibition of cytochrome P450 enzymes (IC50 > 10 μM). Pharmacokinetic (PK) studies across multiple species demonstrated dose-proportional exposure, excellent oral bioavailability, and favorable tissue distribution. Importantly, HDM2004 displayed synergistic antitumor activity when combined with PD-L1 blockade in syngeneic mouse models, while maintaining an acceptable safety profile. Collectively, these data support HDM2004 as a promising preclinical candidate for combination cancer immunotherapy.