Non-ATP Competitive Inhibitor of BCR-ABL for the Therapy of Imatinib- Resistant Cmls; Annual rept. 1 Apr 2007-31 Mar 2008

摘要

We have developed several novel small molecule inhibitors of BCR-ABL that inhibit the proliferation and induce apoptosis of CML cell lines that express the WT or the T315I mutant form of BCR-ABL. These compounds readily induced the downregulation of BCR-ABL auto-phosphorylation and STAT-5 phosphorylation. Using ON044580 as the lead compound, we have carried out chemical modification of the compound to facilitate the oral bio-availability of the compound. This resulted in the derivation of two compounds, ONO45260 and ON044690 which retained the BCR-ABL inhibitory activity of the parent compound. They also retained the ability to inhibit kinase activities of WT and V617F mutant forms of JAK2 and induce apoptosis of leukemic cell lines that express the V617F mutant form of JAK2. We show that ON044850 destroys the Bcr- Abl/Jak2 protein Network, which is a large multi-component signaling structure maintained in an active state by members of the HSP90 chaperone complex. ON044850 causes reduction of STAT3 levels leading to reduced expression of HSP90.