Discovery of quinazoline HPK1 inhibitors with high cellular potency.
Bioorg Med Chem
; 92: 117423, 2023 09 07.
Article
en En
| MEDLINE
| ID: mdl-37531921
ABSTRACT
Hematopoietic progenitor kinase 1 (HPK1) is regarded as a highly validated target in pre-clinical immune oncology. HPK1 has been described as regulating multiple critical signaling pathway in both adaptive and innate cells. In support of this role, HPK1 KO T cells show enhanced sensitivity to TCR activation and HPK1 KO mice display enhanced anti-tumor activity. Taken together, inhibition of HPK1 has the potential to induce enhanced anti-tumor immune response. Herein, we described the discovery of highly potent HPK1 inhibitors starting form a weak HTS hit. Using a structure-based drug design, HPK1 inhibitors exhibiting excellent cellular single-digit nanomolar potency in both proximal (pSLP76) and distal (IL-2) biomarkers along with sustained elevation of IL-2 cytokine secretion were discovered.
Palabras clave
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Receptores de Antígenos de Linfocitos T
/
Interleucina-2
Límite:
Animals
Idioma:
En
Revista:
Bioorg Med Chem
Asunto de la revista:
BIOQUIMICA
/
QUIMICA
Año:
2023
Tipo del documento:
Article