Kinase scaffold repurposing for neglected disease drug discovery: discovery of an efficacious, lapatinib-derived lead compound for trypanosomiasis.
J Med Chem
; 56(10): 3820-32, 2013 May 23.
Article
em En
| MEDLINE
| ID: mdl-23597080
ABSTRACT
Human African trypanosomiasis (HAT) is a neglected tropical disease caused by the protozoan parasite Trypanosoma brucei . Because drugs in use against HAT are toxic and require intravenous dosing, new drugs are needed. Initiating lead discovery campaigns by using chemical scaffolds from drugs approved for other indications can speed up drug discovery for neglected diseases. We demonstrated recently that the 4-anilinoquinazolines lapatinib (GW572016, 1) and canertinib (CI-1033) kill T. brucei with low micromolar EC50 values. We now report promising activity of analogues of 1, which provided an excellent starting point for optimization of the chemotype. Our compound optimization that has led to synthesis of several potent 4-anilinoquinazolines, including NEU617, 23a, a highly potent, orally bioavailable inhibitor of trypanosome replication. At the cellular level, 23a blocks duplication of the kinetoplast and arrests cytokinesis, making it a new chemical tool for studying regulation of the trypanosome cell cycle.
Texto completo:
1
Coleções:
01-internacional
Contexto em Saúde:
3_ND
Base de dados:
MEDLINE
Assunto principal:
Fosfotransferases
/
Quinazolinas
/
Tripanossomicidas
/
Trypanosoma brucei brucei
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Tripanossomíase Africana
/
Descoberta de Drogas
Tipo de estudo:
Prognostic_studies
Limite:
Animals
/
Humans
Idioma:
En
Revista:
J Med Chem
Ano de publicação:
2013
Tipo de documento:
Article