Discovery of TK-642 as a highly potent, selective, orally bioavailable pyrazolopyrazine-based allosteric SHP2 inhibitor.
Acta Pharm Sin B
; 14(8): 3624-3642, 2024 Aug.
Article
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| MEDLINE
| ID: mdl-39234614
ABSTRACT
Src homology-2-containing protein tyrosine phosphatase 2 (SHP2) is a promising therapeutic target for cancer therapy. In this work, we presented the structure-guided design of 5,6-fused bicyclic allosteric SHP2 inhibitors, leading to the identification of pyrazolopyrazine-based TK-642 as a highly potent, selective, orally bioavailable allosteric SHP2 inhibitor (SHP2WT IC50 = 2.7 nmol/L) with favorable pharmacokinetic profiles (F = 42.5%; t 1/2 = 2.47 h). Both dual inhibition biochemical assay and docking analysis indicated that TK-642 likely bound to the "tunnel" allosteric site of SHP2. TK-642 could effectively suppress cell proliferation (KYSE-520 cells IC50 = 5.73 µmol/L) and induce apoptosis in esophageal cancer cells by targeting the SHP2-mediated AKT and ERK signaling pathways. Additionally, oral administration of TK-642 also demonstrated effective anti-tumor effects in the KYSE-520 xenograft mouse model, with a T/C value of 83.69%. Collectively, TK-642 may warrant further investigation as a promising lead compound for the treatment of esophageal cancer.
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Colección:
01-internacional
Base de datos:
MEDLINE
Idioma:
En
Revista:
Acta Pharm Sin B
Año:
2024
Tipo del documento:
Article
País de afiliación:
China