Slamon Mak Cancer Stem Cell Abstract
Drug discovery programs against two different mitotic kinases are being pursued. Both programs follow the same general process flow in which lead optimization experiments culminate in the selection of a single small molecule candidate for advancement to preclinical development. The development candidate then proceeds through a standard series of evaluations to establish its suitability for an IND submission and use in subsequent clinical trials.
CFI-003 was selected as a clinical development candidate and is progressing through investigational new drug application (IND)-enabling studies. Chemistry activity in the past year has included the selection of the fumarate salt as the final salt form, and production of two kilogram-scale clinical batches, the first of which is scheduled to be released at the end of April. The compound is stable when stored under typical storage conditions, and has an impurity profile that is safe for clinical dosing. In cancer models, CFI-003 was shown to be particularly effective against tumors deficient for the tumor suppressor gene PTEN; this is important given that deficiencies in this gene are generally considered to be an indicator of poor prognosis in the clinic. Experiments are ongoing to determine biomarkers of response to CFI-003 for application in the clinic. Other work includes selection and management of contract research organizations (CROs) for critical IND-enabling studies. For example, Pharmatek has been engaged to assist in the development of a drug formulation that enhances the stability of CFI-003, and maximizes bioavailability of the compound when dosed orally. Other CRO work that is ongoing involves in vitro pharmacology experiments geared toward understanding how CFI-003 might interact with co-administered drugs, and performing key toxicology experiments for determination of a safe and effective clinical dose of the compound. An important milestone was reached in the previous reporting period in that the patent application covering CFI-003 was allowed by the US patent office. The CFI-003 IND development team will continue to move the project forward planning for a successful IND submission toward the end of Q1 2013.
The drug discovery efforts in the second program have been focused on improving the pharmacokinetic properties of the lead series molecules while maintaining excellent in vitro activity. Approximately 400 new chemical entities have been synthesized during the last reporting period. Progress to date has been measured by an increase in potency in the biochemical assay and improved anti-proliferative potency in cancer cell growth assays. Activity toward Aurora B has simultaneously been attenuated, and current compounds demonstrate improved selectivity against a diverse panel of kinases. Progress was aided by the acquisition of multiple co-complex x-ray structures which allowed for further refinement of binding models to the target’s active site. Compounds to be qualified for further study must continue to induce an aneuploidy phenotype at least an order of magnitude above the HCT116 (colon adenocarcinoma cell line) GI50, and importantly must also demonstrate adequate plasma levels upon oral dosing. A lead series compound has been shown to have oral efficacy in a cancer model. To follow up this result, additional compounds have been scaled up for testing. Experiments to determine the tolerability have been completed for the latest candidates and further efficacy studies have been initiated. Results from these efficacy studies will aid in the identification of a development candidate for subsequent IND enabling studies.