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

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

  • Blood. 2007 Apr 15;109(8):3470-8. doi: 10.1182/blood-2006-02-005579.
Geoffrey A Bartholomeusz 1 Moshe Talpaz Vaibhav Kapuria Ling Yuan Kong Shimei Wang Zeev Estrov Waldemar Priebe Ji Wu Nicholas J Donato
Affiliations

Affiliation

  • 1 Department of Experimental Therapeutics, University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
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.

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