Structure-activity relationship study of beta-carboline derivatives as haspin kinase inhibitors.
Bioorg Med Chem Lett
; 22(5): 2015-9, 2012 Mar 01.
Article
de En
| MEDLINE
| ID: mdl-22335895
ABSTRACT
Haspin is a serine/threonine kinase that phosphorylates Thr-3 of histone H3 in mitosis that has emerged as a possible cancer therapeutic target. High throughput screening of approximately 140,000 compounds identified the beta-carbolines harmine and harmol as moderately potent haspin kinase inhibitors. Based on information obtained from a structure-activity relationship study previously conducted for an acridine series of haspin inhibitors in conjunction with in silico docking using a recently disclosed crystal structure of the kinase, harmine analogs were designed that resulted in significantly increased haspin kinase inhibitory potency. The harmine derivatives also demonstrated less activity towards DYRK2 compared to the acridine series. In vitro mouse liver microsome stability and kinase profiling of a representative member of the harmine series (42, LDN-211898) are also presented.
Texte intégral:
1
Collection:
01-internacional
Base de données:
MEDLINE
Sujet principal:
Carbolines
/
Protein-Serine-Threonine Kinases
/
Protéines et peptides de signalisation intracellulaire
/
Inhibiteurs de protéines kinases
Limites:
Animals
/
Humans
Langue:
En
Journal:
Bioorg Med Chem Lett
Sujet du journal:
BIOQUIMICA
/
QUIMICA
Année:
2012
Type de document:
Article
Pays d'affiliation:
États-Unis d'Amérique