Discovery of Potent, Selective, and Orally Available IRE1α Inhibitors Demonstrating Comparable PD Modulation to IRE1 Knockdown in a Multiple Myeloma Model.
J Med Chem
; 67(11): 8708-8729, 2024 Jun 13.
Article
em En
| MEDLINE
| ID: mdl-38748820
ABSTRACT
The lack of selective and safe in vivo IRE1α tool molecules has limited the evaluation of IRE1α as a viable target to treat multiple myeloma. Focus on improving the physicochemical properties of a literature compound by decreasing lipophilicity, molecular weight, and basicity allowed the discovery of a novel series with a favorable in vitro safety profile and good oral exposure. These efforts culminated in the identification of a potent and selective in vivo tool compound, G-5758, that was well tolerated following multiday oral administration of doses up to 500 mg/kg. G-5758 demonstrated comparable pharmacodynamic effects to induced IRE1 knockdown as measured by XBP1s levels in a multiple myeloma model (KMS-11).
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Proteínas Serina-Treonina Quinases
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Endorribonucleases
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Mieloma Múltiplo
Limite:
Animals
/
Humans
Idioma:
En
Revista:
J Med Chem
Assunto da revista:
QUIMICA
Ano de publicação:
2024
Tipo de documento:
Article
País de afiliação:
Estados Unidos