Scaffold Hopping Yields a Tricyclic, Orally Available HPK1 Inhibitor That Boosts Anti-PD-1 in Mice
- Starting from a known diaminopyrimidine carboxamide HPK1 inhibitor, structure-guided scaffold hopping and ring-system tuning produced a new tricyclic pyrido[2,1-h]pteridin-6-one core.
- The lead compound, 29, was strongly potent against HPK1 and highly selective across other kinases.
- In cells, it blocked HPK1-driven SLP-76 phosphorylation and strengthened T-cell activation in Jurkat cells and human PBMCs.
- It was well absorbed orally and, combined with anti-PD-1, clearly improved tumor control in a CT26.WT syngeneic mouse model.
💡 Points Based on the abstract
Locking the hinge-binding pharmacophore into a tricycle is a sensible way out of the crowded diaminopyrimidine carboxamide space. Rigidifying the core should pay the conformational penalty up front and help kinome selectivity, which matters because MAP4K relatives are the usual liability. Exposure data and the ring-fused synthetic route would decide how excited I get.