Allosteric TYK2 inhibition: redefining autoimmune disease therapy beyond JAK1-3 inhibitors.
EBioMedicine
; 97: 104840, 2023 Nov.
Article
em En
| MEDLINE
| ID: mdl-37863021
ABSTRACT
JAK inhibitors impact multiple cytokine pathways simultaneously, enabling high efficacy in treating complex diseases such as cancers and immune-mediated disorders. However, their broad reach also poses safety concerns, which have fuelled a demand for increasingly selective JAK inhibitors. Deucravacitinib, a first-in-class allosteric TYK2 inhibitor, represents a remarkable advancement in the field. Rather than competing at kinase domain catalytic sites as classical JAK1-3 inhibitors, deucravacitinib targets the regulatory pseudokinase domain of TYK2. It strikingly mirrors the functional effect of an evolutionary conserved naturally occurring TYK2 variant, P1104A, known to protect against multiple autoimmune diseases yet provide sufficient TYK2-mediated cytokine signalling required to prevent immune deficiency. The unprecedentedly high functional selectivity and efficacy-safety profile of deucravacitinib, initially demonstrated in psoriasis, combined with genetic support, and promising outcomes in early SLE clinical trials make this inhibitor ripe for exploration in other autoimmune diseases for which better, safe, and efficacious treatments are urgently needed.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Psoríase
/
Doenças Autoimunes
/
Inibidores de Janus Quinases
Limite:
Humans
Idioma:
En
Revista:
EBioMedicine
Ano de publicação:
2023
Tipo de documento:
Article
País de afiliação:
Dinamarca