A major theme of this leukemia SPORE application is translational research that focuses on identifying therapeutically relevant targets for anti-leukemic drug discovery. Each of the projects presented in this application is a testament to a strong collaborative effort between clinicians and basic scientists, which interfaces many aspects of translational research, including oncogenic signaling, epigenetic, experimental therapeutics, and immunology. The Medicinal Chemistry Core integrates the expertise of two laboratories, including medicinal chemistry, molecular and cell biology, and molecular pharmacology (Chen), and computational chemistry and structural biology (Li). In the past few years, this program has developed a series of agents targeting different molecular defects clinically relevant to leukemogenesis, two of which are ready to enter clinical trials in 2009. Thus, this core provides a platform to translate basic science findings from each of these projects into the design and synthesis of small-molecule agents for testing individual hypotheses, and adds an important dimension to expedite the translation from bench to the clinic. Specifically, the following three aims constitute the foci of this Medicinal Chemistry Core with initial emphasis on targeting immunomodulation in tumor-specific T cells and natural killer cells (Project 3), and protein phosphatase (PP) 2A (Pilot Project 2), which will be expanded to address other new molecular targets arising from other projects. Overall, our specific aims include:
Aim 1. To carry out lead optimization of lenalidomidie to develop specific immunomodulatory drugs for chronic lymphocytic leukemia (CLL) therapy (in collaboration with Project 3).
Aim 2. To carry out structural optimization of FTY720 to develop novel PP2A-activating agents (in collaboration with Pilot Project 2).
Aim 3. To provide aspects of medicinal chemistry service including custom synthesis, sample preparations, computational chemistry, and structural biology to interested investigators of this SPORE application (all Projects) and other NCI SPORE and P01 investigators. An example of this is providing OSU-HDAC42 to investigators in Projects 4, 5 and Developmental Project 1. Overall, this unique core will provide members of the SPORE a greater opportunity to translate findings into therapeutic options for patients with leukemia.
This Core provides support in synthetic medicinal chemistry and structural biology/computational chemistry to individual projects to translate basic science findings into the design and synthesis of small-molecule agents for hypothesis testing. Lead compounds with therapeutic potential will further undergo structural optimization to develop potent agents for clinical translation.
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|Eisfeld, Ann-Kathrin; Kohlschmidt, Jessica; Mrózek, Krzysztof et al. (2018) Mutation patterns identify adult patients with de novo acute myeloid leukemia aged 60 years or older who respond favorably to standard chemotherapy: an analysis of Alliance studies. Leukemia 32:1338-1348|
|Eisfeld, Ann-Kathrin; Kohlschmidt, Jessica; Mrózek, Krzysztof et al. (2018) NF1 mutations are recurrent in adult acute myeloid leukemia and confer poor outcome. Leukemia 32:2536-2545|
|Eisfeld, A-K; Mrózek, K; Kohlschmidt, J et al. (2017) The mutational oncoprint of recurrent cytogenetic abnormalities in adult patients with de novo acute myeloid leukemia. Leukemia 31:2211-2218|
|Papaioannou, Dimitrios; Shen, Changxian; Nicolet, Deedra et al. (2017) Prognostic and biological significance of the proangiogenic factor EGFL7 in acute myeloid leukemia. Proc Natl Acad Sci U S A 114:E4641-E4647|
|Woyach, Jennifer A; Ruppert, Amy S; Guinn, Daphne et al. (2017) BTKC481S-Mediated Resistance to Ibrutinib in Chronic Lymphocytic Leukemia. J Clin Oncol 35:1437-1443|
|Blum, W; Sanford, B L; Klisovic, R et al. (2017) Maintenance therapy with decitabine in younger adults with acute myeloid leukemia in first remission: a phase 2 Cancer and Leukemia Group B Study (CALGB 10503). Leukemia 31:34-39|
|Mani, R; Yan, R; Mo, X et al. (2017) Non-immunosuppressive FTY720-derivative OSU-2S mediates reactive oxygen species-mediated cytotoxicity in canine B-cell lymphoma. Vet Comp Oncol 15:1115-1118|
|Sekeres, Mikkael A; Othus, Megan; List, Alan F et al. (2017) Randomized Phase II Study of Azacitidine Alone or in Combination With Lenalidomide or With Vorinostat in Higher-Risk Myelodysplastic Syndromes and Chronic Myelomonocytic Leukemia: North American Intergroup Study SWOG S1117. J Clin Oncol 35:2745-2753|
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