Guest guest Posted November 1, 2007 Report Share Posted November 1, 2007 Translational Research Wen-Hwa Lee, PhD - 2008 (Active) - 6097-08 Department of Biological Chemistry, University of California at Irvine, > Irvine, CA US Developing IBR Compounds as Rad51 Recombinase Inhibitors for Leukemia Treatment Imatinib, a potent inhibitor of Bcr-Abl has been successful in treating CML patients but faces two major obstacles. One is the persistence of Bcr-Abl-positive stem cells, which may require long-term imatinib therapy. The other is relapse of the disease due to the emergence of resistance to imatinib. It is hypothesized that combining a Bcr-Abl tyrosine kinase inhibitor with inhibitors of critical downstream effectors could significantly improve CML treatment. Rad51 recombinase, an essential protein for cell proliferation, is a key downstream target of Bcr-Abl kinase, which enhances Rad51 expression through Stat5 as well as activates Rad51 through phosphorylation. We have discovered a novel Rad51 inhibitor, IBR2 that inhibits Rad51 multimerization and activates Rad51 degradation. IBR2 synergizes with imatinib in treating K562 cells as well as Ba/F3-p210 cells. Remarkably, this compound alone induces apoptosis of Ba/F3 cells with imatinib-resistant T315I mutant and significantly prolonged the lifespan of mice carrying Ba/F3-T315I cells. In this application, we plan to generate more effective IBR2 analogues to improve the efficacy of treating CML and acute myeloid leukemia (AML) because 70% of AML have an activated Stat5 that enhances Rad51 expression. It is anticipated that this newly discovered Rad51 inhibitor would be beneficial in treating these leukemias. Zavie (age 69) 67 Shoreham Avenue Ottawa, Canada, K2G 3X3 dxd AUG/99 INF OCT/99 to FEB/00, CHF No meds FEB/00 to JAN/01 Gleevec since MAR/27/01 (400 mg) CCR SEP/01. #102 in Zero Club 2.8 log reduction Sep/05 3.0 log reduction Jan/06 2.9 log reduction Feb/07 3.2 log reduction Jun/07 3.6 log reduction Sep/07 e-mail: zmiller@... Tel: 613-726-1117 Fax: 309-296-0807 Cell: 613-202-0204 ID: zaviem Quote Link to comment Share on other sites More sharing options...
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