Abstract
Myeloproliferative disorders (MPD) are clonal malignancies characterized by overproduction of one or more hematopoietic lineages with relatively normal differentiation. The molecular pathogenesis of several MPDs has been well characterized, and is frequently attributable to mutations that result in constitutive activation of a protein tyrosine kinase. The classic MPDs are subdivided into chronic myeloid leukemia (CML i.e. BCR-ABL+) and the BCR-ABL- classic MPDs, i.e. polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF). Imatinib, which is an inhibitor of the BCR-ABL tyrosine kinase, has been a remarkable success for the treatment of CML. However, a significant proportion of patients chronically treated with imatinib develop resistance due to acquisition of mutations in the kinase domain of BCR-ABL. A novel gain-of-function mutation in the JAK2 tyrosine kinase (JAK2V617F) has been observed in about 95% of patients with PV and 50% of those with either ET or PMF. This mutation has also been found in patients with non-classic MPDs such as refractory anemia with ringed sideroblasts associated with thrombocytosis (RARS-T), chronic neutrophilic leukemia (CNL), atypical CML and chronic myelomonocytic leukemia (CMML) at incidences of 50%, 20%, 20% and 3%, respectively. JAK2V617F has been found to confer erythropoietin-independent growth of the mutant cells in vitro due to deregulation of signaling pathways downstream of JAK2. These findings have opened new avenues for the diagnosis and classification of patients with these disorders, and identify a new molecular target for drug discovery. In our quest to develop targeted therapies for MPD, we screened a compound library of molecules and identified an \#945;-stryl benzyl sulfone, ON044580 that exhibits potent JAK2 inhibitory activity. ON 044580 is a substrate-competitive inhibitor of JAK2 and is unaffected by physiological levels of ATP. ON044580 interferes with IL-3 mediated proliferation pathways that signal via JAK2 to inhibit the growth and survival of Ba/F3-JAK2V617F cells. Growth of two patient cell lines, HEL and SET-2, which express the activating JAK2V617F mutation is also inhibited by ON044580. ON 044580 is also a potent inhibitor of the tyrosine kinase activity of BCR-ABL purified from mammalian cells. Further, ON 044580 inhibits the phosophorylation of BCR-ABL and Stat5 in cultured CML cells. Finally, not only does ON044580 induce apoptosis in cells expressing imanitib-sensitive and imanitib-resistant forms of BCR-ABL, it does so in primary cells from CML patients. Taken together, our results suggest that ON 044580 is a dual JAK2/BCR-ABL kinase inhibitor with therapeutic potential to treat JAK2V617F positive MPDs and CML.
Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 3717.
100th AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO
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