Rational design of multitargeted tyrosine kinase inhibitors: a novel approach.
The non-receptor Src tyrosine kinase is known to cooperate with the epidermal growth factor receptor in a mechanism leading to invasion and metastasis of solid tumours. With the purpose of developing agents targeted to both epidermal growth factor receptor and Src or related kinases, we embarked on the design of chimeric molecules termed combi-molecules capable of blocking both Src and epidermal growth factor receptor. To this end, we have chosen to design molecules containing a quinazoline moiety (directed at epidermal growth factor receptor) and a 7-phenyl-pyrazolopyrimidine (directed at Src). Molecular modelling showed that the optimal position to attach the linker was the 6-position of the quinazoline and the 9-position of the pyrazolopyrimidine. This has led to the synthesis of SB162, SB166 and SB163. SB163 containing the longest linker was the only molecule capable of inducing a dose-dependent inhibition of both Src and epidermal growth factor receptor. SB163 also induced a dose inhibition of Abl and PDGFR.
Barchéchath
Sylvie
S
Cancer Drug Research Laboratory, Department of Medicine, Division of Medical Oncology, McGill University Health Center/Royal Victoria Hospital, 687 Pine Avenue West, Montreal H3A1A1, Quebec, Canada.
Williams
Christopher
C
Saade
Khalil
K
Lauwagie
Sylvia
S
Jean-Claude
Bertrand
B
D018360:Crystallography, X-Ray; D015195:Drug Design; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D011485:Protein Binding; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D011799:Quinazolines / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D019061:src-Family Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*
D008024:Ligands; D011720:Pyrazoles; D011743:Pyrimidines; D011799:Quinazolines; D066246:ErbB Receptors; D019061:src-Family Kinases