The Aurora Kinase Family (AKF) comprises heavily pursued therapeutic targets for cancer because of their intimate involvement in cell division and tumor progression. Numerous therapeutic campaigns have been initiated against the AKF, with promising clinical successes emanating from strategies targeting either Aurora A or Aurora B. However, the US Food and Drug Administration has yet to approve a cancer therapy that targets either Aurora A or B. In an attempt to identify a more viable Aurora B-targeted agent, we have completed preliminary, pre-clinical development of a clinical candidate. The candidate represents the first Aurora B-targeted agent that can be safely administered through an oral dose with statistically significant, anti-tumor efficacy observed at 3.0 mg/kg PO dosing. Through pre-clinical studies, it was determined that the candidate is selective for oncogene-driven cell lines and attains efficacy through Aurora B inhibition. The candidate displayed broad activity against a variety of solid and liquid tumors attaining GI50 values around 1.0 nM. Interestingly, the candidate can potently block acute myeloid leukemia (AML) cell growth as exhibited through inhibition of the HL- 60 AML cell line (GI50 = 0.5 nM), but does not inhibit normal hematopoietic progenitor cells (HSPCs). Importantly, pre-clinical and clinical studies have identified AML as an exceptional candidate for Aurora B inhibition and, accordingly, the candidate has demonstrated immense potential to effectively treat AML. We wish to further progress the clinical candidate for the AML indication because of activity in HL-60 and MOLM-13 AML cell lines and from the mounting pre-clinical and clinical evidence that AML is extensively driven through Aurora B activity. In the following proposal, we will further develop the candidate by completing pilot formulation, additional AML efficacy studies, PK/PD, and toxicity studies. This will acquire pivotal data necessary to justify completing an investigative new drug (IND) package. We have established a robust proof of concept data package for the compound, but specific facets of preclinical development are lacking that warrant additional pre-IND development. With the completion of this proposal, we will have a data package that will merit full IND development that will lead to eventual commercialization of the clinical candidate.
Project Terms: Acute Myelocytic Leukemia; Adverse effects; aqueous; aurora kinase; Back; Bioavailable; Body Weight; Canis familiaris; Cell division; cell growth; Cell Line; Chemistry; Clinical; clinical candidate; Clinical Research; Clinical Trials; Coagulation Process; commercialization; Cyclodextrins; Data; Data Analyses; Dose; drug development; Drug Formulations; Drug Kinetics; drug quality; effective therapy; efficacy study; Excipients; Exhibits; Family; Female; Flow Cytometry; food consumption; Formulation; Generations; Growth; Hematology; Hematopoietic stem cells; Histone H3; HL60; improved; in vivo; inhibitor/antagonist; leukemia; Liquid substance; male; Malignant - descriptor; Malignant Neoplasms; Medicine; Monitor; Nitrogen; No-Observed-Adverse-Effect Level; Normal Cell; novel therapeutics; Oncogenes; Oral; organic acid; Patients; Pharmacodynamics; Phase; Phosphorylation; pre-clinical; preclinical development; preclinical study; Property; Rattus; Research; Salts; Sampling; Serum; Sodium Chloride; Solid; Solubility; success; targeted agent; targeted cancer therapy; Therapeutic; therapeutic target; Toxic effect; Toxicokinetics; tumor; tumor progression; United States Food and Drug Administration; Universities; Work; Xenograft procedure;
