posted on 2022-12-12, 18:38authored byQinda Ye, Kai Liu, Hai-Fen Ye, Jun Pan, Alexander Sokolsky, Anlai Wang, Ke Zhang, Joshua R. Hummel, Ling Kong, Elham Behshad, Xin He, Patricia Conlen, Kristine Stump, Min Ye, Sharon Diamond, Maryanne Covington, Swamy Yeleswaram, Onur Atasoylu, Oleg Vechorkin, Wenqing Yao
In spite of the great success of immune checkpoint inhibitors
in
immune-oncology therapy, an urgent need still exists to identify alternative
approaches to broaden the scope of therapeutic coverage. Hematopoietic
progenitor kinase 1 (HPK1), also known as MAP4K1, functions as a negative
regulator of activation signals generated by the T cell antigen receptor.
Herein we report the discovery of novel pyrazolopyridine derivatives
as selective inhibitors of HPK1. The structure–activity relationship
campaign led to the discovery of compound 16, which has
shown promising enzymatic and cellular potency with encouraging kinome
selectivity. The outstanding pharmacokinetic profiles of 16 in rats and monkeys supported further evaluations of its efficacy
and safety in preclinical models.