Synthesis and pharmacological characterization of novel and selective FLT3 inhibitors

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Numerous studies demonstrate that constitutively active Fms-Like Tyrosine Kinase-3 (FLT3) mutations causally contribute to the development and progression of acute myeloid leukemia (AML). These mutations frequently reside in the juxtamembrane domain of (FLT3). In addition to these internal tandem duplications (ITD), mutations in the kinase domain play a role. Accordingly, various clinical studies show that inhibitors of the tyrosine kinase activity of FLT3 are useful for the treatment of AML. However, the current therapy with known FLT3 inhibitors leads to secondary FLT3 mutations in a substantial proportion of patients. These cause a loss of inhibitor efficacy and a lost benefit for the patients. We are now able to offer the new substance BS228. This compound has an unprecedented specificity and at the same time the highest potency known to date. Furthermore, BS228 acts against therapy-associated mutants of FLT3-ITD. In our proposed project we want to consolidate our present, promising data on BS228. We will employ structural and cell biological studies using permanent cell lines and primary leukemia cells. Animal models shall also be included. Chemically modified derivatives of BS228 that aim to yield irreversible inhibitors and to further improve the selectivity, solubility, and bioavailability will be generated and analyzed. Based on our existing work, we also want to investigate further rational combination regimen against FLT3-ITD-positive AML. Since it has not been fully understood, which signaling pathways are modulated upon the inhibition of FLT3-ITD and whether they are relevant for the growth and survival of AML cells, we additionally want to define these parameters. These preclinical investigations aim to bring BS228 and potentially even more active ingredients of this type into clinical application. Moreover, we want to gain new insights into the biology of FLT3 and its inhibition at the molecular level.