Discovery and optimization of 5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one derivatives as mTORC1/mTORC2 dual inhibitors.
Bioorg Chem
; 92: 103232, 2019 11.
Article
em En
| MEDLINE
| ID: mdl-31526911
ABSTRACT
New potent mTORC1/mTORC2 dual inhibitors, 5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one derivatives, were obtained by optimizing functional groups on our previously reported PI3Kα inhibitor. All the target compounds were synthesized and structural optimization on the structure of the lead compound based on cytotoxic activity. The results showed that some of the target compounds exhibited moderate to high cytotoxic activity against cell line U87MG and PC-3. The activities against mTOR kinase were investigated and the compound 12q showed excellent activity with an IC50 value of 54â¯nM in the same level of the positive control BEZ235 with IC50 value of 55â¯nM under the same test conditions. The western blot and cell cycle results demonstrate that compound 12q is a candidate as an mTORC1/mTORC2 dual-target inhibitor. The theoretical calculations were also performed to better understanding the binding modes of the compound 12q in the mTOR active site.
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MEDLINE
Assunto principal:
Pirimidinas
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Proliferação de Células
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Descoberta de Drogas
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Alvo Mecanístico do Complexo 1 de Rapamicina
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Alvo Mecanístico do Complexo 2 de Rapamicina
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Antineoplásicos
Idioma:
En
Ano de publicação:
2019
Tipo de documento:
Article