4-Amino-6-arylamino-pyrimidine-5-carbaldehyde hydrazones as potent ErbB-2/EGFR dual kinase inhibitors.
Bioorg Med Chem Lett
; 18(16): 4615-9, 2008 Aug 15.
Article
in En
| MEDLINE
| ID: mdl-18653333
ABSTRACT
Members of a novel class of 4-amino-6-arylamino-pyrimidine-5-carbaldehyde hydrazones were identified as potent dual ErbB-2/EGFR kinase inhibitors using concept-guided design approach. These compounds inhibited the growth of ErbB-2 over-expressing human tumor cell lines (BT474, N87, and SK-BR-3) in vitro. Compound 15 emerged as a key lead and showed significant ability to inhibit growth factor-induced receptor phosphorylation in SK-BR-3 cells (IC(50)=54 nM) and cellular proliferation in vitro (IC(50)=14, 58, and 58 nM for BT474, N87, and SK-BR-3 respectively). The X-ray co-crystal structure of EGFR with a close analog (17) was determined and validated our design rationale.
Full text:
1
Database:
MEDLINE
Main subject:
Pyrimidines
/
Chemistry, Pharmaceutical
/
Receptor, ErbB-2
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Protein Kinase Inhibitors
/
ErbB Receptors
/
Hydrazones
Type of study:
Prognostic_studies
Limits:
Animals
/
Humans
Language:
En
Year:
2008
Type:
Article