Discovery of a potent and selective JAK1-targeting PROTAC degrader with anti-tumor activities.
Bioorg Med Chem Lett
; 109: 129838, 2024 Sep 01.
Article
em En
| MEDLINE
| ID: mdl-38838918
ABSTRACT
Aberrant activation of the JAK-STAT pathway is evident in various human diseases including cancers. Proteolysis targeting chimeras (PROTACs) provide an attractive strategy for developing novel JAK-targeting drugs. Herein, a series of CRBN-directed JAK-targeting PROTACs were designed and synthesized utilizing a JAK1/JAK2 dual inhibitor-momelotinib as the warhead. The most promising compound 10c exhibited both good enzymatic potency and cellular antiproliferative effects. Western blot analysis revealed that compound 10c effectively and selectively degraded JAK1 in a proteasome-dependent manner (DC50 = 214 nM). Moreover, PROTAC 10c significantly suppressed JAK1 and its key downstream signaling. Together, compound 10c may serve as a novel lead compound for antitumor drug discovery.
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Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Proliferação de Células
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Janus Quinase 1
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Proteólise
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Antineoplásicos
Idioma:
En
Ano de publicação:
2024
Tipo de documento:
Article