Discovery of Thiazolo[5,4-c]pyridine Derivatives as Novel Hematopoietic Progenitor Kinase 1 Inhibitors for Tumor Immunotherapy.
TL;DR
This new inhibitor exhibits potent HPK1 inhibition, high selectivity within the MAP4K family, along with improved metabolic properties and reduced hERG liability, and demonstrates robust monotherapy efficacy and synergizes with an anti-PD-1 antibody or an anti-PD-L1/IL-15 immunocytokine prodrug.
Abstract
Hematopoietic progenitor kinase 1 (HPK1) functions as an intracellular negative regulator of T-cell receptor signaling, and its inhibition has emerged as a promising strategy to counteract T-cell exhaustion and potentiate antitumor immunity. Through rational structural optimization of a recently reported HPK1 inhibitor 12 bearing a monocyclic thiazole skeleton, we developed a new inhibitor 23 featuring a bicyclic thiazolo[5,4-c]pyridine component. This new inhibitor exhibits potent HPK1 inhibition, high selectivity within the MAP4K family, along with improved metabolic properties and reduced hERG liability. Mechanistically, compound 23 effectively suppressed HPK1 activation in cells and restored TCR signaling, resulting in a marked enhancement of T-cell function in both naïve and antigen-specific responses. In xenograft tumor models, compound 23 demonstrated robust monotherapy efficacy and synergizes with an anti-PD-1 antibody or an anti-PD-L1/IL-15 immunocytokine prodrug. The balanced potency, good safety and optimized pharmacokinetics warrant compound 23 for further preclinical evaluation.