Targeting MLL As Anticancer Therapy for Infant Acute Lymphoblastic Leukemia

DESCRIPTION (provided by applicant): Advances in treatment strategies have increased the long-term survival of children with acute lymphoblastic leukemia (ALL). However, the outlook of infants with ALL remains dismal with long-term survival rates of only 30-50%. Therefore, new treatments are desperately needed. Translocation of the mixed lineage leukemia (MLL) transcription factor is found in 70-80% of infant ALL cases and is associated with poor treatment outcome, suggesting that targeting MLL may have clinical benefit. Through cell-based small molecule screening, we identified small molecule SM7, which specifically kills multiple types of MLL-leukemia with little effect on non-MLL cancers or normal cells, including those of hematopoietic origin. However, maximum killing is achieved at 10 ?M and molecule appears to be structurally unstable. Therefore, the goal of this proposal is to structurally optimize SM7 for both efficacy and stability using synthetic chemistry guided by stability testing and MLL-specificity characterization in order to generate a potential lead compound(s) for development into an anticancer drug for the treatment of MLL-leukemia. PUBLIC HEALTH RELEVANCE: Infant acute lymphoblastic leukemia often contains MLL gene translocations (70-80%), which are associated with poor treatment response. There is currently no effective treatment due to the lack of efficacy of current available drugs and severe toxic side effects caused by highly intensive therapy. Development of an MLL-leukemia specific drug should provide a more efficacious and less toxic alternative to current treatment strategies and, thus, has major implications for the therapeutic management for all children with this aggressive disease.