degrasyn and Blast-Crisis

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.

Topics: Animals; Apoptosis; Benzamides; Blast Crisis; Cell Line, Tumor; Cyanoacrylates; Drug Screening Assays, Antitumor; Fusion Proteins, bcr-abl; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Leukemic; Imatinib Mesylate; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Mice; Mice, Nude; Neoplasms, Experimental; Nitriles; Piperazines; Point Mutation; Protein Kinase Inhibitors; Pyridines; Pyrimidines; Tumor Stem Cell Assay