Rational design of highly selective spleen tyrosine kinase inhibitors.
J Med Chem
; 55(23): 10414-23, 2012 Dec 13.
Article
de En
| MEDLINE
| ID: mdl-23151054
ABSTRACT
A novel approach to design selective spleen tyrosine kinase (Syk) inhibitors is described. Inhibition of spleen tyrosine kinase has attracted much attention as a mechanism for the treatment of autoimmune diseases such as asthma, rheumatoid arthritis, and SLE. Fostamatinib, a Syk inhibitor that successfully completed phase II clinical trials, also exhibits some undesirable side effects. More selective Syk inhibitors could offer safer, alternative treatments. Through a systematic evaluation of the kinome, we identified Pro455 and Asn457 in the Syk ATP binding site as a rare combination among sequence aligned kinases and hypothesized that optimizing the interaction between them and a Syk inhibitor molecule would impart high selectivity for Syk over other kinases. We report the structure-guided identification of three series of selective spleen tyrosine kinase inhibitors that support our hypothesis and offer useful guidance to other researchers in the field.
Texte intégral:
1
Collection:
01-internacional
Base de données:
MEDLINE
Sujet principal:
Rate
/
Protein-tyrosine kinases
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Inhibiteurs de protéines kinases
Type d'étude:
Guideline
Limites:
Humans
Langue:
En
Journal:
J Med Chem
Sujet du journal:
QUIMICA
Année:
2012
Type de document:
Article
Pays d'affiliation:
États-Unis d'Amérique