Novel imatinib derivatives with altered specificity between Bcr-Abl and FMS, KIT, and PDGF receptors.
Imatinib is a clinically important ATP analogue inhibitor that targets the tyrosine kinase domain of the intracellular Abl kinase and the PDGF receptor family. Imatinib has revolutionised the treatment of chronic myeloid leukaemia, which is caused by the oncogene Bcr-Abl and certain solid tumours that harbor oncogenic mutations of the PDGF receptor family. As a leading kinase inhibitor, imatinib also provides an excellent model system to investigate how changes in drug design impact biological activity, which is an important consideration for rational drug design. Herein we report a new series of imatinib derivatives that in general have greater activity against the family of PDGF receptors and poorer activity against Abl, as a result of modifications of the phenyl and N-methylpiperazine rings. These new compounds provide a platform for further drug development against the therapeutically important PDGF receptor family and they also provide insight into the engineering of drugs with altered biological activity.
Skobridis
Konstantinos
K
Department of Chemistry, Section of Organic Chemistry and Biochemistry, University of Ioannina, 45110 Ioannina, Greece. kskobrid@cc.uoi.gr
Kinigopoulou
Maria
M
Theodorou
Vassiliki
V
Giannousi
Emilia
E
Russell
Alison
A
Chauhan
Rakhee
R
Sala
Roberta
R
Brownlow
Nicola
N
Kiriakidis
Serafim
S
Domin
Jan
J
Tzakos
Andreas G
AG
Dibb
Nick J
NJ
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D001549:Benzamides; D001665:Binding Sites; D045744:Cell Line, Tumor; D003198:Computer Simulation; D015195:Drug Design; D016044:Fusion Proteins, bcr-abl / Q000378:metabolism*; D006801:Humans; D000068877:Imatinib Mesylate; D020014:K562 Cells; D051379:Mice; D010766:Phosphorylation; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism*; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000378:metabolism*; D017479:Receptors, Platelet-Derived Growth Factor / Q000378:metabolism*; D013379:Substrate Specificity
D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit; D016186:Receptor, Macrophage Colony-Stimulating Factor; D017479:Receptors, Platelet-Derived Growth Factor; D016044:Fusion Proteins, bcr-abl