Discovery of a Potent and Selective Coactivator Associated Arginine Methyltransferase 1 (CARM1) Inhibitor by Virtual Screening.
J Med Chem
; 59(14): 6838-47, 2016 07 28.
Article
en En
| MEDLINE
| ID: mdl-27390919
ABSTRACT
Protein arginine methyltransferases (PRMTs) represent an emerging target class in oncology and other disease areas. So far, the most successful strategy to identify PRMT inhibitors has been to screen large to medium-size chemical libraries. Attempts to develop PRMT inhibitors using receptor-based computational methods have met limited success. Here, using virtual screening approaches, we identify 11 CARM1 (PRMT4) inhibitors with ligand efficiencies ranging from 0.28 to 0.84. CARM1 selective hits were further validated by orthogonal methods. Two structure-based rounds of optimization produced 27 (SGC2085), a CARM1 inhibitor with an IC50 of 50 nM and more than hundred-fold selectivity over other PRMTs. These results indicate that virtual screening strategies can be successfully applied to Rossmann-fold protein methyltransferases.
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Evaluación Preclínica de Medicamentos
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Inhibidores Enzimáticos
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Proteínas Adaptadoras de Señalización CARD
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Guanilato Ciclasa
Tipo de estudio:
Diagnostic_studies
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Risk_factors_studies
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Screening_studies
Límite:
Humans
Idioma:
En
Año:
2016
Tipo del documento:
Article