Activation of a novel Bcr/Abl destruction pathway by WP1130 induces apoptosis of chronic myelogenous leukemia cells.

Abstract

Imatinib mesylate (Gleevec) is effective therapy against Philadelphia chromosome-positive leukemia, but resistance develops in all phases of the disease. Bcr/Abl point mutations and other alterations reduce the kinase inhibitory activity of imatinib mesylate; thus, agents that target Bcr/Abl through unique mechanisms may be needed. Here we describe the activity of WP1130, a small molecule that specifically and rapidly down-regulates both wild-type and mutant Bcr/Abl protein without affecting bcr/abl gene expression in chronic myelogenous leukemia (CML) cells. Loss of Bcr/Abl protein correlated with the onset of apoptosis and reduced phosphorylation of Bcr/Abl substrates. WP1130 did not affect Hsp90/Hsp70 ratios within the cells and did not require the participation of the proteasomal pathway for loss of Bcr/Abl protein. WP1130 was more effective in reducing leukemic versus normal hematopoietic colony formation and strongly inhibited colony formation of cells derived from patients with T315I mutant Bcr/Abl-expressing CML in blast crisis. WP1130 suppressed the growth of K562 heterotransplanted tumors as well as both wild-type Bcr/Abl and T315I mutant Bcr/Abl-expressing BaF/3 cells transplanted into nude mice. Collectively, our results demonstrate that WP1130 reduces wild-type and T315I mutant Bcr/Abl protein levels in CML cells through a unique mechanism and may be useful in treating CML.

• Authors: Geoffrey A Bartholomeusz, Moshe Talpaz, Vaibhav Kapuria, Ling Yuan Kong, Shimei Wang, Zeev Estrov, Waldemar Priebe, Ji Wu, Nicholas J Donato
• Journal: Blood (Blood) Vol. 109 Issue 8 Pg. 3470-8 (Apr 15 2007) ISSN: 0006-4971 [Print] United States
• PMID: 17202319 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Benzamides
• Cyanoacrylates
• Nitriles
• Piperazines
• Protein Kinase Inhibitors
• Pyridines
• Pyrimidines
• degrasyn
• Imatinib Mesylate
• Fusion Proteins, bcr-abl

Topics

• Animals
• Apoptosis (drug effects, genetics)
• Benzamides
• Blast Crisis (drug therapy, enzymology, genetics, pathology)
• Cell Line, Tumor
• Cyanoacrylates
• Drug Screening Assays, Antitumor
• Fusion Proteins, bcr-abl (antagonists & inhibitors, biosynthesis, genetics)
• Gene Expression Regulation, Enzymologic
• Gene Expression Regulation, Leukemic (drug effects)
• Imatinib Mesylate
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive (drug therapy, enzymology, genetics, pathology)
• Mice
• Mice, Nude
• Neoplasms, Experimental (drug therapy, enzymology, genetics, pathology)
• Nitriles (pharmacology)
• Piperazines (pharmacology)
• Point Mutation
• Protein Kinase Inhibitors (pharmacology)
• Pyridines (pharmacology)
• Pyrimidines (pharmacology)
• Tumor Stem Cell Assay