Discovery of a Novel Series of Imidazopyrazine Derivatives as Potent SHP2 Allosteric Inhibitors.
ACS Med Chem Lett
; 14(2): 156-162, 2023 Feb 09.
Article
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| MEDLINE
| ID: mdl-36793438
ABSTRACT
Protein tyrosine phosphatase SHP2 is an oncogenic protein that can regulate different cytokine receptor and receptor tyrosine kinase signaling pathways. We report here the identification of a novel series of SHP2 allosteric inhibitors having an imidazopyrazine 6,5-fused heterocyclic system as the central scaffold that displays good potency in enzymatic and cellular assays. SAR studies led to the identification of compound 8, a highly potent SHP2 allosteric inhibitor. X-ray studies showed novel stabilizing interactions with respect to known SHP2 inhibitors. Subsequent optimization allowed us to identify analogue 10, which possesses excellent potency and a promising PK profile in rodents.
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Colección:
01-internacional
Banco de datos:
MEDLINE
Idioma:
En
Revista:
ACS Med Chem Lett
Año:
2023
Tipo del documento:
Article
País de afiliación:
Italia