Acute myeloid leukemia (AML) is a form of cancer in which the normal development of blood cells is blocked and the cells abnormally proliferate. AML affects both children and adults with an incidence of approximately 7000 new patients in the U.S. each year. A substantial portion of AMLs cases has extremely dire prognosis. Although considerable progress has been made in understanding the causes of AML, the drugs currently used to treat these diseases are little changed over the past 40 years and yield disappointing results, with an overall five-year survival rate of AML patients less than 20%. The ultimate goal of this project work is to identify new class of drugs for AML that specifically target mechanisms that the tumor cells use to promote their growth advantage. Specifically, recent studies have shown that histone H3 K4 methyltransferase MLL and its enzymatic activity are essential for both leukemic transformation and for survival of leukemic stem cells. Furthermore, the H3 K4 enzymatic activity of MLL is tightly regulated by the WDR5-MLL protein-protein interaction. We hypothesize that small- molecule inhibitors designed to block the WDR5-MLL interaction may be effective in inhibition of the MLL H3 K4 methyltransferase activity and may have the therapeutic potential to be developed as a completely new class of therapy for the treatment of acute leukemia. Toward this goal we have teamed up with a group of investigators with complementary expertise and proven record to design and develop highly potent and specific small-molecule inhibitors of the WDR5-MLL interaction using a powerful structure-based design strategy. Our preliminary data have provided the critical proof-of-concept for this approach and laid the foundation for the success of this project.

Public Health Relevance

Acute myeloid leukemia (AML) is a form of blood cancer and affects both children and adults with an incidence of approximately 7000 new patients in the U.S. each year. A substantial portion of AML cases has extremely dire prognosis and new and effective therapies are urgently needed. This project seeks the discovery and development of small-molecule inhibitors of the WDR5-MLL protein-protein interaction as a completely new class of therapy for the treatment of AML and other types of human cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA177307-02
Application #
8650277
Study Section
Special Emphasis Panel (ZRG1-BCMB-H (02))
Program Officer
Misra, Raj N
Project Start
2013-04-09
Project End
2017-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
2
Fiscal Year
2014
Total Cost
$454,167
Indirect Cost
$158,484
Name
University of Michigan Ann Arbor
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Cao, Fang; Townsend, Elizabeth C; Karatas, Hacer et al. (2014) Targeting MLL1 H3K4 methyltransferase activity in mixed-lineage leukemia. Mol Cell 53:247-61