Characterization of potent inhibitors of the Bcr-Abl and the c-kit receptor tyrosine kinases.
The early stage of chronic myelogenous leukemia (CML) is caused by the tyrosine kinase Bcr-Abl. Imatinib mesylate (also known as STI-571 and Gleevec), a tyrosine kinase inhibitor, has shown encouraging results in CML clinical trials and has become a paradigm for targeted cancer therapeutics. Recent reports of resistance to imatinib argue for further development of therapies for CML. During studies of signal transduction, we observed that the pyrido[2,3-d]pyrimidine src tyrosine kinase inhibitor PD173955 inhibited Bcr-Abl-dependent cell growth. Subsequently, a related compound, PD180970, was reported as a potent inhibitor of Bcr-Abl. We have compared the potency of these two compounds and four other analogues with imatinib on Bcr-Abl-dependent cell growth, cytokine-dependent cell growth, and tyrosine kinase inhibition. PD173955 inhibited Bcr-Abl-dependent cell growth with an IC(50) of 2-35 nM in different cell lines. Fluorescence-activated cell-sorting analyses of cells treated with PD173955 showed cell cycle arrest in G(1). PD173955 has an IC(50) of 1-2 nM in kinase inhibition assays of Bcr-Abl, and in cellular growth assays it inhibits Bcr-Abl-dependent substrate tyrosine phosphorylation. Of the six pyrido[2,3-d]pyrimidine analogues studied, PD166326 was the most potent inhibitor of Bcr-Abl-dependent cell growth. PD173955 inhibited kit ligand-dependent c-kit autophosphorylation (IC(50) = approximately 25 nM) and kit ligand-dependent proliferation of M07e cells (IC(50) = 40 nM) but had a lesser effect on interleukin 3-dependent (IC(50) = 250 nM) or granulocyte macrophage colony-stimulating factor (IC(50) = 1 microM)-dependent cell growth. These compounds are potent inhibitors of both the Bcr-Abl and c-kit receptor tyrosine kinases and deserve further study as potential treatments for both CML and for diseases in which c-kit has a role.
Wisniewski
David
D
Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
Lambek
Caryl L
CL
Liu
Chongyuan
C
Strife
Annabel
A
Veach
Darren R
DR
Nagar
Bhushan
B
Young
Matthew A
MA
Schindler
Thomas
T
Bornmann
William G
WG
Bertino
Joseph R
JR
Kuriyan
John
J
Clarkson
Bayard
B
D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D016044:Fusion Proteins, bcr-abl; D016193:G1 Phase / Q000187:drug effects; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D008958:Models, Molecular; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000502:physiology; D019009:Proto-Oncogene Proteins c-kit / Q000187:drug effects* / Q000378:metabolism; D011728:Pyridones / Q000737:chemistry / Q000494:pharmacology*; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology*; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; C403095:PD 173955; D011728:Pyridones; D011743:Pyrimidines; D011505:Protein-Tyrosine Kinases; D019009:Proto-Oncogene Proteins c-kit; D020794:Receptor Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl; C410732:PD 180970