Discovery of indenopyrazoles as EGFR and VEGFR-2 tyrosine kinase inhibitors by in silico high-throughput screening

Taikou Usui; Hyun Seung Ban; Junpei Kawada; Takatsugu Hirokawa; Hiroyuki Nakamura

doi:10.1016/j.bmcl.2007.10.084

Discovery of indenopyrazoles as EGFR and VEGFR-2 tyrosine kinase inhibitors by in silico high-throughput screening

Bioorg Med Chem Lett. 2008 Jan 1;18(1):285-8. doi: 10.1016/j.bmcl.2007.10.084. Epub 2007 Oct 30.

Authors

Taikou Usui¹, Hyun Seung Ban, Junpei Kawada, Takatsugu Hirokawa, Hiroyuki Nakamura

Affiliation

¹ Department of Chemistry, Faculty of Science, Gakushuin University, Tokyo 171-8588, Japan.

PMID: 17983745
DOI: 10.1016/j.bmcl.2007.10.084

Abstract

A series of indenopyrazoles 8 and 9 were designed and synthesized as EGFR tyrosine kinase inhibitors by in silico high-throughput screening. Compounds 8b and 8d showed significant inhibition of A431 cell growth (GI50 = 0.062 and 0.057 microM, respectively). Compounds 8b and 9a showed inhibitory activity toward both EGFR and VEGFR-2 (KDR) tyrosine kinases, whereas 8d inhibited VEGFR-2 tyrosine kinase, exclusively.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Binding Sites
Cell Line, Tumor
Combinatorial Chemistry Techniques
Crystallography, X-Ray
Drug Design
ErbB Receptors / antagonists & inhibitors*
ErbB Receptors / chemistry
Humans
Kinetics
Models, Molecular
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry*
Protein Kinase Inhibitors / pharmacology*
Pyrazoles / chemical synthesis
Pyrazoles / chemistry*
Pyrazoles / pharmacology*
Structure-Activity Relationship
Substrate Specificity
Vascular Endothelial Growth Factor Receptor-2 / antagonists & inhibitors*
Vascular Endothelial Growth Factor Receptor-2 / chemistry

Substances

Protein Kinase Inhibitors
Pyrazoles
ErbB Receptors
Vascular Endothelial Growth Factor Receptor-2