ALKYNYL AMINOISOQUINOLINES, NOVEL FLT3 KINASE INHIBITORS WITH POTENT ACTIVITY AGAINST ACUTE MYELOID LEUKEMIA

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dc.contributor.advisorSintim, Herman Oen_US
dc.contributor.authorMa, Xiaochuen_US
dc.contributor.departmentChemistryen_US
dc.contributor.publisherDigital Repository at the University of Marylanden_US
dc.contributor.publisherUniversity of Maryland (College Park, Md.)en_US
dc.date.accessioned2019-06-22T05:31:58Z
dc.date.available2019-06-22T05:31:58Z
dc.date.issued2018en_US
dc.description.abstractAcute myeloid leukemia (AML) is a type of blood cancer. If not properly treated, this subclass of leukemia can progress quickly, and be fatal after a few months. Aberrantly expressed FMS (Feline McDonough Sarcoma)-like tyrosine kinase (FLT3) is observed in approximately 30% of AML patients, so it is a promising molecular target for AML. Midostaurin (commercial name, Rydapt) was the first approved FDA drug for AML that targets FLT3. However, Midostaurin, is not a single agent drug and is only effective when used in combination with other cytotoxic drugs. Therefore, there is a need for FLT3 inhibitors that are effective as a single agent. In Chapter 2, the synthesis of a series of amidine-acetylene-isoquinoline-3-amines is described. Amidine-acetylene-isoquinoline-3-amine compounds have the potential to serve new FLT3 inhibitors with inhibition IC50 values in the nanomolar region against wild type FLT3, FLT3-ITD (internal tandem duplications) and FLT3-D835Y (a tyrosine kinase domain mutant, commonly found in AML patients). Amidine drugs are generally not orally bioavailable, the synthesis of amide-acetylene-isoquinoline-3-amines, our second generation FLT3 inhibitors are described in Chapters 3 and 4. The amide-acetylene-isoquinolines inhibit FLT3-driven AML cell lines with single digit nanomolar IC50 values and are either comparable to or better than most FLT3 inhibitors reported to date.en_US
dc.identifierhttps://doi.org/10.13016/zplf-pvqz
dc.identifier.urihttp://hdl.handle.net/1903/22157
dc.language.isoenen_US
dc.subject.pqcontrolledOrganic chemistryen_US
dc.subject.pquncontrolledaminoisoquinolineen_US
dc.subject.pquncontrolledAMLen_US
dc.subject.pquncontrolledFLT3en_US
dc.subject.pquncontrolledkinase inhibitoren_US
dc.titleALKYNYL AMINOISOQUINOLINES, NOVEL FLT3 KINASE INHIBITORS WITH POTENT ACTIVITY AGAINST ACUTE MYELOID LEUKEMIAen_US
dc.typeDissertationen_US

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