Design and synthesis of highly selective Janus kinase 3 covalent inhibitors for the treatment of rheumatoid arthritis.
Arch Pharm (Weinheim)
; 357(6): e2300753, 2024 Jun.
Article
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| MEDLINE
| ID: mdl-38442328
ABSTRACT
Selective inhibition of Janus kinase 3 (JAK3) is a promising strategy for the treatment of autoimmune diseases. Based on the discovery of a hydrophobic pocket unutilized between the lead compound RB1 and the JAK3 protein, a series of covalent JAK3 inhibitors were prepared by introducing various aromatic fragments to RB1. Among them, J1b (JAK3 IC50 = 7.2 nM, other JAKs IC50 > 1000 nM) stood out because of its low toxicity (MTD > 2 g/kg) and superior anti-inflammatory activity in Institute of Cancer Research mice. Moreover, the acceptable bioavailability (F% = 31.69%) ensured that J1b displayed excellent immune regulation in collagen-induced arthritis mice, whose joints in the high-dose group were almost recovered to a normal state. Given its clear kinase selectivity (Bmx IC50 = 539.9 nM, other Cys909 kinases IC50 > 1000 nM), J1b was nominated as a highly selective JAK3 covalent inhibitor, which could be used to safely treat arthritis and other autoimmune diseases.
Palabras clave
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Artritis Experimental
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Artritis Reumatoide
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Diseño de Fármacos
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Inhibidores de Proteínas Quinasas
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Janus Quinasa 3
Límite:
Animals
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Humans
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Male
Idioma:
En
Revista:
Arch Pharm (Weinheim)
Año:
2024
Tipo del documento:
Article
País de afiliación:
China