Design, Synthesis and Antitumor Activity of a Novel Class of SHP2 Allosteric Inhibitors with a Furanyl Amide-Based Scaffold.
J Med Chem
; 67(15): 13305-13323, 2024 Aug 08.
Article
em En
| MEDLINE
| ID: mdl-39066713
ABSTRACT
SHP2 plays a critical role in modulating tumor growth and PD-1-related signaling pathway, thereby serving as an attractive antitumor target. To date, no antitumor drugs targeting SHP2 have been approved, and hence, the search of SHP2 inhibitors with new chemical scaffolds is urgently needed. Herein, we developed a novel SHP2 allosteric inhibitor SDUY038 with a furanyl amide scaffold, demonstrating potent binding affinity (KD = 0.29 µM), enzymatic activity (IC50 = 1.2 µM) and similar binding interactions to SHP099. At the cellular level, SDUY038 exhibited pan-antitumor activity (IC50 = 7-24 µM) by suppressing pERK expression. Furthermore, SDUY038 significantly inhibited tumor growth in both xenograft and organoid models. Additionally, SDUY038 displayed acceptable bioavailability (F = 14%) and half-life time (t1/2 = 3.95 h). Conclusively, this study introduces the furanyl amide scaffold as a novel class of SHP2 allosteric inhibitors, offering promising lead compounds for further development of new antitumor therapies targeting SHP2.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Desenho de Fármacos
/
Proteína Tirosina Fosfatase não Receptora Tipo 11
/
Amidas
/
Antineoplásicos
Limite:
Animals
/
Humans
Idioma:
En
Ano de publicação:
2024
Tipo de documento:
Article