A JAK tyrosine kinase and pseudokinase Co-inhibition strategy combines enhanced potency and on-demand activation.
Eur J Med Chem
; 250: 115198, 2023 Mar 15.
Article
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| MEDLINE
| ID: mdl-36805946
ABSTRACT
Janus tyrosine kinase (JAK) inhibitors have been on the market for several years, but their use is limited by drug resistance and intolerable side effects. Herein, we propose a novel strategy of JAK tyrosine kinase (TK) and pseudokinase (PK) domain co-inhibition system to consolidate robust JAK inhibition and on-demand activation. A photoexcited prodrug PAT-SIL-TG-1&AT exhibits the synergy effects of TK-PK co-inhibition and enable the spatiotemporal control of JAK2 signaling. The hypoxia-activated prodrug HAT-SIL-TG-1&AT significantly inhibited HEL cells proliferation and downregulated phosphorylated STAT3/5 under hypoxic conditions. Importantly, HAT-SIL-TG-1&AT showed synergistic antitumor effects and selectively inhibited the JAK-STAT signaling in tumor tissues in vivo. This work demonstrates a viable solution to achieve superior JAK2 inhibition, and provides an inspiration for other kinases containing PK domain.
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Banco de datos:
MEDLINE
Asunto principal:
Tirosina
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Idioma:
En
Revista:
Eur J Med Chem
Año:
2023
Tipo del documento:
Article
País de afiliación:
China