Generation of highly potent DYRK1A-dependent inducers of human ß-Cell replication via Multi-Dimensional compound optimization.
Bioorg Med Chem
; 28(1): 115193, 2020 01 01.
Article
em En
| MEDLINE
| ID: mdl-31757680
ABSTRACT
Small molecule stimulation of ß-cell regeneration has emerged as a promising therapeutic strategy for diabetes. Although chemical inhibition of dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) is sufficient to enhance ß-cell replication, current lead compounds have inadequate cellular potency for in vivo application. Herein, we report the clinical stage anti-cancer kinase inhibitor OTS167 as a structurally novel, remarkably potent DYRK1A inhibitor and inducer of human ß-cell replication. Unfortunately, OTS167's target promiscuity and cytotoxicity curtails utility. To tailor kinase selectivity towards DYRK1A and reduce cytotoxicity we designed a library of fifty-one OTS167 derivatives based upon a modeled structure of the DYRK1A-OTS167 complex. Indeed, derivative characterization yielded several leads with exceptional DYRK1A inhibition and human ß-cell replication promoting potencies but substantially reduced cytotoxicity. These compounds are the most potent human ß-cell replication-promoting compounds yet described and exemplify the potential to purposefully leverage off-target activities of advanced stage compounds for a desired application.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Proteínas Tirosina Quinases
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Proteínas Serina-Treonina Quinases
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Inibidores de Proteínas Quinases
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Bibliotecas de Moléculas Pequenas
Limite:
Humans
Idioma:
En
Ano de publicação:
2020
Tipo de documento:
Article