We have used an ultra high throughput screen of the NIH Molecular Libraries Small Molecule Repository (MLSMR) using a luciferase reporter cell-based assay, follow-up mechanistic studies, and medicinal chemistry optimization efforts to discover a potent and selective inhibitor of expression of the transcription factor Kr�ppel-like factor 5 (KLF5). Malignant epithelial cells in intestinal crypts have elevated levels of KLF5, also called intestinal-enriched Kr�ppel-like factor (IKLF). While many antitumor agents target proteins regulated by transcription factors, small molecule therapeutics rarely lessen the production of a transcription factor itself by design, an appealing strategy since one transcription factor can stimulate multiple pathways aiding tumor progression, with devastating consequences. We herein disclose a potent and selective small molecule inhibitor of KLF5 expression that reduces proliferation of most types of colon cancer cells. SAR studies and optimization of lead-like and drug-like properties are discussed.  Preliminary in vivo efficacy studies will also be presented.  We anticipate that this tool compound will aid efforts to elucidate KLF5's role in regulating cellular proliferation and tumor formation in the intestinal epithelium. Further, we hope that this compound may help demonstrate that specifically lowering expression levels of a transcription factor can be effective means of cancer chemotherapy.

Small molecule inhibitors of KLF5 expression: Tools for targeting colorectal cancer

245th National Meeting (2013)

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