Discovery of Pyrazolopyridine Derivatives as HPK1 Inhibitors.
ACS Med Chem Lett
; 14(1): 5-10, 2023 Jan 12.
Article
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| MEDLINE
| ID: mdl-36655125
ABSTRACT
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.
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Colección:
01-internacional
Base de datos:
MEDLINE
Idioma:
En
Revista:
ACS Med Chem Lett
Año:
2023
Tipo del documento:
Article
País de afiliación:
Estados Unidos