Discovery of a Novel Pyrido[2,1- h ]pteridin-6-one Derivative as a Potent and Orally Bioavailable HPK1 Inhibitor
Yun Wu, Chenliang Shi, Chao Wu, Ziping Qi, Rui Jin, Qingwang Liu, Qianmao Liang, Aoli Wang, Wenchao Wang, Beilei Wang, Qingsong Liu, Jing LiuAbstract
Hematopoietic progenitor kinase 1 (HPK1), a key negative regulator of T-cell activation, represents a highly promising yet challenging target for cancer immunotherapy. To date, no HPK1 inhibitor has received marketing approval, underscoring the need for innovative scaffolds. Here, we report the structure-based drug discovery of a potent HPK1 inhibitor featuring a unique pyrido[2,1-h]pteridin-6-one core. Through a series of chemical modifications, including scaffold hopping and ring-system optimization, starting from a known diaminopyrimidine carboxamide structure, we successfully constructed this key tricyclic core. The lead compound 29 exhibited remarkable potency against HPK1, along with outstanding selectivity. It effectively suppressed HPK1-mediated SLP-76 phosphorylation, thereby enhancing T-cell activation in both Jurkat cells and human PBMCs. Moreover, 29 displayed excellent oral bioavailability and markedly enhanced antitumor efficacy in combination with anti-PD-1 in a CT26.WT syngeneic mouse model. Collectively, these findings identify a novel, potent, and selective HPK1 inhibitor, offering a promising candidate for advancing cancer immunotherapy.