Here we report the discovery of ON044580, an α-benzoyl styryl
benzyl sulfide that possesses potent inhibitory activity against two unrelated
kinases, JAK2 and BCR-ABL, and exhibits cytotoxicity to human
tumor cells derived from
chronic myelogenous leukemia (CML) and myelodysplasia (MDS) patients or cells harboring a mutant JAK2
kinase. This novel spectrum of activity is explained by the non-
ATP-competitive inhibition of JAK2 and BCR-ABL
kinases. ON044580 inhibits mutant JAK2
kinase and the proliferation of JAK2(V617F)-positive leukemic cells and blocks the IL-3-mediated phosphorylation of JAK2 and STAT5. Interestingly, this compound also directly inhibits the
kinase activity of both wild-type and
imatinib-resistant (T315I) forms of the BCR-ABL
kinase. Finally, ON044580 effectively induces apoptosis of
imatinib-resistant CML patient cells. The apparently unrelated JAK2 and BCR-ABL
kinases share a common substrate, STAT5, and such substrate competitive inhibitors represent an alternative therapeutic strategy for development of new inhibitors. The novel mechanism of
kinase inhibition exhibited by ON044580 renders it effective against mutant forms of
kinases such as the BCR-ABL(T315I) and JAK2(V617F). Importantly, ON044580 selectively reduces the number of
aneuploid cells in primary bone marrow samples from
monosomy 7 MDS patients, suggesting another regulatory cascade amenable to this agent in these aberrant cells. Data presented suggest that this compound could have multiple therapeutic applications including
monosomy 7 MDS,
imatinib-resistant CML, and myeloproliferative
neoplasms that develop resistance to
ATP-competitive agents.