Discovery of Pyrazolo[1,5-a]pyridine Derivatives as Potent and Selective PI3Kγ/δ Inhibitors.
J Med Chem
; 67(17): 15199-15219, 2024 Sep 12.
Article
em En
| MEDLINE
| ID: mdl-39163191
ABSTRACT
PI3Kγ and PI3Kδ plays critical roles in exerting immunosuppression by targeting regulatory T cells and myeloid cells. Dual inhibition of PI3Kγ and PI3Kδ has emerged as a novel therapeutic strategy for cancer immunotherapy. We herein report a series of pyrazolopyridine derivatives with distinct scaffolds as potent and selective dual inhibitors of PI3Kγ and PI3Kδ. Among them, 20e (IHMT-PI3K-315) displays an IC50 value of 4.0 and 9.1 nM against PI3Kγ and PI3Kδ respectively in biochemical assays. Meanwhile, it potently inhibits PI3Kγ and PI3Kδ-mediated phosphorylation of AKT S473 with EC50 values of 0.028 and 0.013 µM in cellular assays. In addition, 20e exhibits a favorable selectivity profile in protein kinases at 1 µM. In bone marrow-derived macrophages (BMDM), 20e can repolarize the M2 phenotype to the M1 phenotype. In vivo, 20e demonstrates acceptable pharmacokinetic properties and suppresses tumor growth in a MC38 syngeneic mouse model.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Pirazóis
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Piridinas
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Classe I de Fosfatidilinositol 3-Quinases
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Classe Ib de Fosfatidilinositol 3-Quinase
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Inibidores de Fosfoinositídeo-3 Quinase
Idioma:
En
Revista:
J Med Chem
/
J. med. chem
/
Journal of medicinal chemistry
Assunto da revista:
QUIMICA
Ano de publicação:
2024
Tipo de documento:
Article