CBF inhibitors

Given that CBF and the AR pathways intersect and that CBF has been shown to regulate gene expression changes associated with tumorigenesis and metastasis in prostate cancer cell lines, it seems reasonable to identify small molecules that can inhibit CBF function. Small molecules that interfere with the interaction between the RUNX proteins and CBFp were recently described. In the first of these studies, the 3D structure of CBFp was solved using NMR and the RUNX1 binding interface was determined [67]. This information was then used to perform a virtual chemical screen and using that information, allosteric inhibitors of CBFp were identified. The most potent inhibitor, "17", inhibited proliferation of the ME-1 cell line, a line derived from a patient with acute myelomonocytic leukemia containing the inv(16), by about 40% and showed very little cytotoxicity [67]. Treatment of cells with 100 |im concentrations of Inhibitor 17 reduced RUNX1 DNA binding by about 30%. Thus, compound 17 binds to a site removed from the heterodimerization interface and produces moderate changes in CBF DNA binding and cellular proliferation. These data suggest that allosteric inhibitors of protein complex formation could be useful for probing CBF's role in cancer.

A recent approach to identify a role for CBF in prostate and ovarian cancer provides compelling evidence that CBF is a druggable target. Davis and co-workers showed that CBFp -specific shRNAs inhibited the malignant phenotype of prostate and ovarian cancer cell lines [68]. Cell lines displaying 70% reduction in CBFp were unable to grow in an anchorage independent manner and did not form xenograft tumors in mice. Gene array data (Agilent whole genome array) gathered during this study suggested that CBF-mediated gene expression was inhibited. Bioinformatic searches for RUNX DNA binding sites in the promoter regions of the differentially expressed genes revealed that of the 200 genes that exhibited altered expression, over 20% contained multiple putative RUNX binding sites (analyzed using the consensus TGT/CGGT) within their upstream regulatory regions [68]. EMSA was used to confirm a loss in CBF DNA binding activity [68]. These data clearly demonstrate that inhibition of CBFp expression leads to a reduction in CBF activity and that CBF activity is required for the transformed phenotype.

The DNA binding activity of recombinant CBF is amenable to high throughput screening (HTS) assays and a recent screen of the NIH Clinical Collection Library has identified compounds that inhibit CBF (Davis and Meyers, unpublished data). The CBFp siRNAs and compounds identified via HTS or virtual screens show promise as tools for discovery and as molecules that can be further developed into small molecule therapeutics in prostate cancer.

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