Scientists Achieve Small Molecule Inhibition of Aberrant Transcription Factor at Root of Recurring Acute Myeloid Leukemia (AML)

A novel molecule designed by scientists at the University of Massachusetts Medical School and the University of Virginia inhibits progression of a hard-to-treat form of recurring acute myeloid leukemia (AML) in patient tissue. The small molecule is one of the first designed to specifically target a cancer-causing transcription factor. Previously thought to be an undruggable target, this strategy may be used to design other novel molecules that can specifically inhibit cancer-causing transcription factors. Details of the work were published in the February 13, 2015 issue of Science. The article is titled “A Small-Molecule Inhibitor of the Aberrant Transcription Factor CBFβ-SMMHC Delays Leukemia in Mice.” Transcription factors are single- or multi-protein complexes that regulate transcription of DNA into messenger RNA and gene expression by binding to regions on the genome next to a gene. Mutations in transcription factors can result in altered gene expression programs that give way to new, cancer-causing functions. Although these aberrant transcription factors are promising targets for new therapeutics, the complexity of interrupting very specific protein-to-protein interactions has made it difficult to find small molecules or design drugs that treat these transcription factor-related cancers. "When we look at inhibitors, they usually target an enzyme or receptor. There aren't a lot of good examples of transcription factor inhibitors in clinical trials," said Lucio H. Castilla, Ph.D., Associate Professor of Molecular, Cell, and Cancer Biology at the U-Mass Medical School, and co-leader of the study. "Here, we've used our extensive knowledge of a mutant transcription factor found in a subset for acute myeloid leukemia patients to design a molecule that can specifically sequester only the oncogenic mutant.
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