Colony stimulating factor-1 receptor as a target for small molecule inhibitors.
Imatinib, dasatinib, sunitinib, CEP-701, and PKC-412, ATP-competitive small molecule inhibitors of type III receptor tyrosine kinases c-KIT and/or FLT3, were evaluated for binding to the closely related receptor, FMS, by docking into models of inactive and active conformations of the FMS kinase domain. To confirm the docking predictions, the drugs were tested for their activity and selectivity in inhibiting cell proliferation and FMS phosphorylation upon stimulation by the FMS ligand, CSF-1. All five drugs inhibited FMS activity. Imatinib, dasatinib and CEP-701 represent three different types of interactions determining drug potency and selectivity.
School of Biomedical Sciences, University of Newcastle, Callaghan, NSW 2308, Australia.
Baratali
B
Mashkani
Renate
R
Griffith
Leonie K
LK
Ashman
D001549:Benzamides; D001665:Binding Sites; D002227:Carbazoles / Q000737:chemistry / Q000494:pharmacology; D003198:Computer Simulation; D000069439:Dasatinib; D015195:Drug Design; D005663:Furans; D006801:Humans; D006860:Hydrogen Bonding; D000068877:Imatinib Mesylate; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology; D010879:Piperazines / Q000737:chemistry / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology; D011758:Pyrroles / Q000737:chemistry / Q000494:pharmacology; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019311:Staurosporine / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D000077210:Sunitinib; D013844:Thiazoles / Q000737:chemistry / Q000494:pharmacology
D001549:Benzamides; D002227:Carbazoles; D005663:Furans; D007211:Indoles; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011758:Pyrroles; D013844:Thiazoles; D000068877:Imatinib Mesylate; C119379:lestaurtinib; D016186:Receptor, Macrophage Colony-Stimulating Factor; D019311:Staurosporine; C059539:midostaurin; D000069439:Dasatinib; D000077210:Sunitinib