Discovery of (R)-5-((5-(1-methyl-1H-pyrazol-4-yl)-4-(methylamino)pyrimidin-2-yl)amino)-3-(piperidin-3-yloxy)picolinonitrile, a novel CHK1 inhibitor for hematologic malignancies.
Eur J Med Chem
; 173: 44-62, 2019 Jul 01.
Article
em En
| MEDLINE
| ID: mdl-30986571
ABSTRACT
Through virtual screening, we identified the lead compound MCL1020, which exhibited modest CHK1 inhibitory activity. Then a series of 5-(pyrimidin-2-ylamino)picolinonitrile derivatives as CHK1 inhibitors were discovered by further rational optimization. One promising molecule, (R)-17, whose potency was one of the best, had an IC50 of 0.4â¯nM with remarkable selectivity (>4300-fold CHK1 vs. CHK2). Compound (R)-17 effectively inhibited the growth of malignant hematopathy cell lines especially Z-138 (IC50 0.013⯵M) and displayed low affinity for hERG (IC50â¯>â¯40⯵M). Moreover, (R)-17 significantly suppressed the tumor growth in Z-138â¯cell inoculated xenograft model (20â¯mg/kg I.V., TGIâ¯=â¯90.29%) as a single agent with body weight unaffected. Taken together, our data demonstrated compound (R)-17 could be a promising drug candidate for the treatment of hematologic malignancies.
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MEDLINE
Assunto principal:
Neoplasias Hematológicas
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Inibidores de Proteínas Quinases
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Descoberta de Drogas
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Quinase 1 do Ponto de Checagem
Idioma:
En
Ano de publicação:
2019
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Article