Discovery of a new potent bisamide FMS kinase inhibitor.
FMS is a type III receptor tyrosine kinase that binds to the macrophage or monocyte colony stimulating factor (M-CSF or CSF-1). Signal transduction through that binding results in survival, proliferation, and differentiation of monocyte/macrophage lineage. In this study, we report the discovery of a new potent inhibitor of FMS kinase. The synthesized pyrrolo[3,2-c]pyridine derivative (compound 1) was initially tested at a single concentration of 1 microM against 47 different kinases. At this concentration, the% inhibitions of the enzymatic activities of FMS and KDR kinases were 90% and 71%, respectively, while the inhibition in activity was less than 58% for all of the other kinases. For compound 1, the IC(50) values against FMS and KDR were 96 and 1058 nM, respectively. So, compound 1 was found to be 11 times more selective for FMS kinase than KDR kinase. Compound 1 can be used as a promising lead for the development of new selective inhibitors of FMS kinase, which can be used as useful therapeutic tools for treatment of several inflammatory and cancer disorders.
El-Gamal
Mohammed I
MI
Biomaterials Center, Korea Institute of Science and Technology, PO Box 131, Cheongryang, Seoul 130-650, Republic of Korea.
Jung
Myung-Ho
MH
Oh
Chang-Hyun
CH
D000577:Amides / Q000737:chemistry* / Q000494:pharmacology*; D002460:Cell Line; D055808:Drug Discovery; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000037:antagonists & inhibitors*; D015398:Signal Transduction
D000577:Amides; D016186:Receptor, Macrophage Colony-Stimulating Factor