Preclinical studies of Selective and Orally Bioavailable Aurora B Inhibitors for the Treatment of AML

ABSTRACTThe Aurora Kinase FamilyAKFcomprises heavily pursued therapeutic targets for cancer because of their intimate involvement in cell division and tumor progressionNumerous therapeutic campaigns have been initiated against the AKFwith promising clinical successes emanating from strategies targeting either Aurora A or Aurora BHoweverthe US Food and Drug Administration has yet to approve a cancer therapy that targets either Aurora A or BIn an attempt to identify a more viable Aurora B targeted agentwe have completed preliminarypre clinical development of a clinical candidateThe candidate represents the first Aurora B targeted agent that can be safely administered through an oral dose with statistically significantanti tumor efficacy observed atmg kg PO dosingThrough pre clinical studiesit was determined that the candidate is selective for oncogene driven cell lines and attains efficacy through Aurora B inhibitionThe candidate displayed broad activity against a variety of solid and liquid tumors attaining GIvalues aroundnMInterestinglythe candidate can potently block acute myeloid leukemiaAMLcell growth as exhibited through inhibition of the HLAML cell lineGInMbut does not inhibit normal hematopoietic progenitor cellsHSPCsImportantlypre clinical and clinical studies have identified AML as an exceptional candidate for Aurora B inhibition andaccordinglythe candidate has demonstrated immense potential to effectively treat AMLWe wish to further progress the clinical candidate for the AML indication because of activity in HLand MOLMAML cell lines and from the mounting pre clinical and clinical evidence that AML is extensively driven through Aurora B activityIn the following proposalwe will further develop the candidate by completing pilot formulationadditional AML efficacy studiesPK PDand toxicity studiesThis will acquire pivotal data necessary to justify completing an investigative new drugINDpackageWe have established a robust proof of concept data package for the compoundbut specific facets of preclinical development are lacking that warrant additional pre IND developmentWith the completion of this proposalwe will have a data package that will merit full IND development that will lead to eventual commercialization of the clinical candidate PROJECT NARRATIVEAn orally administered Aurora B inhibitor has been identified that can potentially offer acute myeloid leukemiaAMLpatients a more effective treatmentAdministration of the therapy has been considerably improved over previous treatmentsand the therapy is highly selective for malignant growthThe completion of the proposed research will help this breakthrough medicine reach AML patients quickly and safely