Design, synthesis, and biological evaluation of 2-substituted-pyridin-4-yl macrocyclic derivatives as new selective HPK1 inhibitors.

Hematopoietic progenitor kinase 1 (HPK1) is a negative regulator of T-cell receptor (TCR) signaling and a promising therapeutic target in immunotherapy. Herein, based on the reported HPK1 inhibitor Compound K, a series of 2-substituted-pyridin-4-yl macrocyclic HPK1 inhibitors was designed and synthesized through structure-based drug design and macrocyclization strategies. Detailed SAR studies led to the discovery of compound 2 t, which exhibits excellent HPK1 inhibitory activity (IC = 1.

Discovery of Macrocycle-Based HPK1 Inhibitors for T-Cell-Based Immunotherapy.

Hematopoietic progenitor kinase 1 (HPK1) is a negative regulator of T-cell activation, and targeting HPK1 is considered a promising strategy for improving responses to antitumor immune therapies. The biggest challenge of HPK1 inhibitor design is to achieve a higher selectivity to GLK, an HPK1 homology protein as a positive regulator of T-cell activation. Herein, we report the design of a series of macrocycle-based HPK1 inhibitors via a conformational constraint strategy.