Discovery of SY-5609: A Selective, Noncovalent Inhibitor of CDK7.
J Med Chem
; 65(2): 1458-1480, 2022 01 27.
Article
en En
| MEDLINE
| ID: mdl-34726887
ABSTRACT
CDK7 has emerged as an exciting target in oncology due to its roles in two important processes that are misregulated in cancer cells cell cycle and transcription. This report describes the discovery of SY-5609, a highly potent (sub-nM CDK7 Kd) and selective, orally available inhibitor of CDK7 that entered the clinic in 2020 (ClinicalTrials.gov Identifier NCT04247126). Structure-based design was leveraged to obtain high selectivity (>4000-times the closest off target) and slow off-rate binding kinetics desirable for potent cellular activity. Finally, incorporation of a phosphine oxide as an atypical hydrogen bond acceptor helped provide the required potency and metabolic stability. The development candidate SY-5609 displays potent inhibition of CDK7 in cells and demonstrates strong efficacy in mouse xenograft models when dosed as low as 2 mg/kg.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Neoplasias de la Mama
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Ciclo Celular
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Quinasas Ciclina-Dependientes
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Inhibidores de Proteínas Quinasas
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Descubrimiento de Drogas
Límite:
Animals
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Female
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Humans
Idioma:
En
Revista:
J Med Chem
Asunto de la revista:
QUIMICA
Año:
2022
Tipo del documento:
Article
País de afiliación:
Estados Unidos