A major theme of this leukemia SPORE application is translational research that focuses on identifying therapeufically 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 nterfaces many aspects of translational research, including oncogenic signaling, epigenefics, experimental therapeufics, 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 tesfing 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 targefing immunomodulafion 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 opfimizafion of lenalidomidie to develop specific immunomodulatory drugs for chronic lymphocytic leukemia (CLL) therapy (in collaboration with Project 3).
Aim 2. To carry out structural opfimization 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 preparafions, computational chemistry, and structural biology to interested investigators of this SPORE application (all Projects) and other NCI SPORE and POl 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 opfions 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 translafion.
|Mims, Alice S; Mishra, Anjali; Orwick, Shelley et al. (2018) A novel regimen for relapsed/refractory adult acute myeloid leukemia using a KMT2A partial tandem duplication targeted therapy: results of phase 1 study NCI 8485. Haematologica 103:982-987|
|Walker, Christopher J; Oakes, Christopher C; Genutis, Luke K et al. (2018) Genome-wide association study identifies an acute myeloid leukemia susceptibility locus near BICRA. Leukemia :|
|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|
|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|
|Park, I-K; Blum, W; Baker, S D et al. (2017) E3 ubiquitin ligase Cbl-b activates the p53 pathway by targeting Siva1, a negative regulator of ARF, in FLT3 inhibitor-resistant acute myeloid leukemia. Leukemia 31:502-505|
|Papaioannou, Dimitrios; Nicolet, Deedra; Volinia, Stefano et al. (2017) Prognostic and biologic significance of long non-coding RNA profiling in younger adults with cytogenetically normal acute myeloid leukemia. Haematologica 102:1391-1400|
|Eisfeld, Ann-Kathrin; Kohlschmidt, Jessica; Mrózek, Krzysztof et al. (2017) Mutational Landscape and Gene Expression Patterns in Adult Acute Myeloid Leukemias with Monosomy 7 as a Sole Abnormality. Cancer Res 77:207-218|
|Eisfeld, A-K; Kohlschmidt, J; Schwind, S et al. (2017) Mutations in the CCND1 and CCND2 genes are frequent events in adult patients with t(8;21)(q22;q22) acute myeloid leukemia. Leukemia 31:1278-1285|
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