2009-140 – Inhibitors of Inv(16) Leukemia

Executive SummaryUniversity of Virginia researchers have discovered novel compounds that can be used for the targeted treatment of the inv(16) subtype of Acute Myeloid Leukemia (AML), improving upon existing nonspecific chemotherapies. These compounds have the promise to vastly improve patients92 therapy tolerance, survival rates and relapse rates. BackgroundThe American Cancer Society estimates 12,810 new cases of AML and 9,000 AML-related deaths in 2009. AML sufferers face a five-year survival rate of only approximately 50 percent and a relapse rate of approximately 33 percent. Characterized by the rapid growth of abnormal while blood cells, AML can be caused by a number of genetic abnormalities, including chromosomal translocations, inversions and deletions. A genetic alteration in chromosome 16 causes the AML subtype inv(16), creating a fusion protein with abnormal function. This condition presents symptoms characteristic of AML, such as fatigue, increased propensity for bruising and increased risk of infection.Because patient relapse requires blood or marrow stem cell transplantation from a compatible donor, there is a significant need for new, targeted therapies aimed at specific genetic abnormalities and diseases. Current chemotherapy treatments, however, affect many cell types in the body beyond cancer cells and are therefore known to cause several severe side effects. The discovery of Gleevec to treat Chronic Myelogenous Leukemia (CML), used to treat patients with the Philadelphia chromosome mutation, shows the promise of targeting specific genotypes. About the InventionJohn H. Bushweller, Ph.D., and colleagues at the University of Virginia have designed chemical inhibitors of the inv(16) fusion protein that exhibit great specificity while having no other effect on normal cellular function. The researchers have mapped the compounds92 binding site and verified the protein96protein interaction disruption in vitro. The lead compounds specifically cause cell death in AML inv(16) human tissue culture cells. In addition, the lead compounds show potent cytotoxic activity against AML inv(16) cells derived from human patient samples. Preliminary pharmacokinetics testing in mice is under way to determine compound half-lives and direct future analog generation. Current lead compounds will soon be tested in a mouse AML inv(16) model.AdvantagesThis invention has the potential to dramatically improve AML patient outcomes by:Virtually eliminating the incidence of serious side effects that often result from current cytoxic therapies (due to the compounds92 ability to specifically target the fusion protein) Significantly decreasing remission incidence Significantly increasing five-year patient survival rates Joshua P. Mauldin josh@uvapf.org (434) 243-7183

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