PHA-680626 exhibits anti-proliferative and pro-apoptotic activity on Imatinib-resistant chronic myeloid leukemia cell lines and primary CD34+ cells by inhibition of both Bcr-Abl tyrosine kinase and Aurora kinases.

Abstract

Emergence of resistance to Imatinib complicates the treatment of chronic myeloid leukemia (CML). Second-generation Bcr-Abl inhibitors are capable to overcome resistance mediated by most mutations except T315I. As this mutation is causative for approximately 20% of clinically observed resistances, the need for novel treatment strategies becomes obvious. Here, we report on a novel kinase inhibitor PHA-680626 exhibiting strong inhibitory activity on both Bcr-Abl and Aurora kinases. Significant anti-proliferative and pro-apoptotic effects were observed in human BCR-ABL positive cell lines and murine BaF3 cells ectopically expressing wt BCR-ABL or the Imatinib-resistant BCR-ABL mutants M351T, E255K and, T315I. Treatment with PHA-680626 decreased phosphorylation of CrkL and histone H3. As CrkL represents a typical downstream target of Bcr-Abl while histone H3 phosphorylation is an indicator for Aurora kinase B activity, these findings indicate that effects of PHA-680626 are mediated via inhibition of both pathways. Moreover, high anti-proliferative activity of PHA-680626 was observed in primary CD34+ cells derived from CML patients at diagnosis or in blast crisis as well as from an individual harbouring the T315I mutation. Thus, both Bcr-Abl and Aurora kinase inhibition contribute to the efficacy of PHA-680626 against Imatinib-resistant BCR-ABL positive leukemias, particularly those harbouring the T315I mutation.

• Authors: Artur Gontarewicz, Stefan Balabanov, Gunhild Keller, Jens Panse, Philippe Schafhausen, Carsten Bokemeyer, Walter Fiedler, Jürgen Moll, Tim H Brümmendorf
• Journal: Leukemia research (Leuk Res) Vol. 32 Issue 12 Pg. 1857-65 (Dec 2008) ISSN: 0145-2126 [Print] England
• PMID: 18514829 (Publication Type: Journal Article)

Chemical References

• Antigens, CD
• Antigens, CD34
• Antineoplastic Agents
• Benzamides
• PHA 680626
• Piperazines
• Pyrazoles
• Pyrimidines
• Pyrroles
• Imatinib Mesylate
• Protein-Tyrosine Kinases
• Fusion Proteins, bcr-abl
• AURKB protein, human
• Aurora Kinase B
• Aurora Kinases
• Protein Serine-Threonine Kinases

Topics

• Antigens, CD (drug effects)
• Antigens, CD34 (drug effects)
• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Aurora Kinase B
• Aurora Kinases
• Benzamides
• Cell Division (drug effects)
• Cell Line, Tumor
• Drug Resistance, Neoplasm
• Fusion Proteins, bcr-abl
• Humans
• Imatinib Mesylate
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive (enzymology, pathology)
• Piperazines (pharmacology)
• Protein Serine-Threonine Kinases (antagonists & inhibitors)
• Protein-Tyrosine Kinases (antagonists & inhibitors)
• Pyrazoles (pharmacology)
• Pyrimidines (pharmacology)
• Pyrroles (pharmacology)