Discovery of Pyrazolopyridine Derivatives as HPK1 Inhibitors.
Qinda 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
Author Information
Qinda Ye: Incyte Research Institute, 1801 Augustine Cut-Off, Wilmington, Delaware 19803, United States. ORCID
Kai Liu: Incyte Research Institute, 1801 Augustine Cut-Off, Wilmington, Delaware 19803, United States. ORCID
Hai-Fen Ye: Incyte Research Institute, 1801 Augustine Cut-Off, Wilmington, Delaware 19803, United States.
Jun Pan: Incyte Research Institute, 1801 Augustine Cut-Off, Wilmington, Delaware 19803, United States.
Alexander Sokolsky: Incyte Research Institute, 1801 Augustine Cut-Off, Wilmington, Delaware 19803, United States. ORCID
Anlai Wang: Incyte Research Institute, 1801 Augustine Cut-Off, Wilmington, Delaware 19803, United States.
Ke Zhang: Incyte Research Institute, 1801 Augustine Cut-Off, Wilmington, Delaware 19803, United States.
Joshua R Hummel: Incyte Research Institute, 1801 Augustine Cut-Off, Wilmington, Delaware 19803, United States.
Ling Kong: Incyte Research Institute, 1801 Augustine Cut-Off, Wilmington, Delaware 19803, United States.
Elham Behshad: Incyte Research Institute, 1801 Augustine Cut-Off, Wilmington, Delaware 19803, United States.
Xin He: Incyte Research Institute, 1801 Augustine Cut-Off, Wilmington, Delaware 19803, United States.
Patricia Conlen: Incyte Research Institute, 1801 Augustine Cut-Off, Wilmington, Delaware 19803, United States.
Kristine Stump: Incyte Research Institute, 1801 Augustine Cut-Off, Wilmington, Delaware 19803, United States.
Min Ye: Incyte Research Institute, 1801 Augustine Cut-Off, Wilmington, Delaware 19803, United States.
Sharon Diamond: Incyte Research Institute, 1801 Augustine Cut-Off, Wilmington, Delaware 19803, United States.
Maryanne Covington: Incyte Research Institute, 1801 Augustine Cut-Off, Wilmington, Delaware 19803, United States.
Swamy Yeleswaram: Incyte Research Institute, 1801 Augustine Cut-Off, Wilmington, Delaware 19803, United States.
Onur Atasoylu: Incyte Research Institute, 1801 Augustine Cut-Off, Wilmington, Delaware 19803, United States.
Oleg Vechorkin: Incyte Research Institute, 1801 Augustine Cut-Off, Wilmington, Delaware 19803, United States.
Wenqing Yao: Incyte Research Institute, 1801 Augustine Cut-Off, Wilmington, Delaware 19803, United States.
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 , which has shown promising enzymatic and cellular potency with encouraging kinome selectivity. The outstanding pharmacokinetic profiles of in rats and monkeys supported further evaluations of its efficacy and safety in preclinical models.
References
ACS Med Chem Lett. 2021 Dec 08;13(1):84-91
[PMID: 35059127]
