Discovery of novel serine palmitoyltransferase inhibitors as cancer therapeutic agents.
Bioorg Med Chem
; 26(9): 2452-2465, 2018 05 15.
Article
en En
| MEDLINE
| ID: mdl-29669694
ABSTRACT
We pursued serine palmitoyltransferase (SPT) inhibitors as novel cancer therapeutic agents based on a correlation between SPT inhibition and growth suppression of cancer cells. High-throughput screening and medicinal chemistry efforts led to the identification of structurally diverse SPT inhibitors 4 and 5. Both compounds potently inhibited SPT enzyme and decreased intracellular ceramide content. In addition, they suppressed cell growth of human lung adenocarcinoma HCC4006 and acute promyelocytic leukemia PL-21, and displayed good pharmacokinetic profiles. Reduction of 3-ketodihydrosphingosine, the direct downstream product of SPT, was confirmed under in vivo settings after oral administration of compounds 4 and 5. Their anti-tumor efficacy was observed in a PL-21 xenograft mouse model. These results suggested that SPT inhibitors might have potential to be effective cancer therapeutics.
Palabras clave
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Piperidinas
/
Pirazoles
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Inhibidores Enzimáticos
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Serina C-Palmitoiltransferasa
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Antineoplásicos
Límite:
Animals
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Humans
Idioma:
En
Año:
2018
Tipo del documento:
Article