CGP 57148, a tyrosine kinase inhibitor, inhibits the growth of cells expressing BCR-ABL, TEL-ABL, and TEL-PDGFR fusion proteins.
CGP 57148 is a compound of the 2-phenylaminopyrimidine class that selectively inhibits the tyrosine kinase activity of the ABL and the platelet-derived growth factor receptor (PDGFR) protein tyrosine kinases. We previously showed that CGP 57148 selectively kills p210BCR-ABL-expressing cells. To extend these observations, we evaluated the ability of CGP 57148 to inhibit other activated ABL tyrosine kinases, including p185BCR-ABL and TEL-ABL. In cell-based assays of ABL tyrosine phosphorylation, inhibition of ABL kinase activity was observed at concentrations similar to that reported for p210BCR-ABL. Consistent with the in vitro profile of this compound, the growth of cells expressing activated ABL protein tyrosine kinases was inhibited in the absence of exogenous growth factor. Growth inhibition was also observed with a p185BCR-ABL-positive acute lymphocytic leukemia (ALL) cell line generated from a Philadelphia chromosome-positive ALL patient. As CGP 57148 inhibits the PDGFR kinase, we also showed that cells expressing an activated PDGFR tyrosine kinase, TEL-PDGFR, are sensitive to this compound. Thus, this compound may be useful for the treatment of a variety of BCR-ABL-positive leukemias and for treatment of the subset of chronic myelomonocytic leukemia patients with a TEL-PDGFR fusion protein.
Carroll
M
M
Division of Hematology and Medical Oncology, Oregon Health Sciences University, Portland, Oregon 97201-3098, USA.
Ohno-Jones
S
S
Tamura
S
S
Buchdunger
E
E
Zimmermann
J
J
Lydon
N B
NB
Gilliland
D G
DG
Druker
B J
BJ
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001549:Benzamides; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000032:analysis*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D016044:Fusion Proteins, bcr-abl / Q000032:analysis*; D000068877:Imatinib Mesylate; D051379:Mice; D016374:Oncogene Proteins v-abl / Q000032:analysis*; D010879:Piperazines / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D050783:Proto-Oncogene Proteins c-ets; D011743:Pyrimidines / Q000494:pharmacology*; D017479:Receptors, Platelet-Derived Growth Factor / Q000032:analysis*; D012097:Repressor Proteins; D014157:Transcription Factors / Q000032:analysis*; D000097764:ETS Translocation Variant 6 Protein
D000970:Antineoplastic Agents; D001549:Benzamides; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D016044:Fusion Proteins, bcr-abl; D000068877:Imatinib Mesylate; D016374:Oncogene Proteins v-abl; D010879:Piperazines; D011505:Protein-Tyrosine Kinases; D050783:Proto-Oncogene Proteins c-ets; D011743:Pyrimidines; D017479:Receptors, Platelet-Derived Growth Factor; D012097:Repressor Proteins; D014157:Transcription Factors; D000097764:ETS Translocation Variant 6 Protein