Transcription Factor Inhibitors May Help Combat Acute Myeloid Leukemia

Researchers have now come up with a novel molecule that may inhibit the progression of recurring acute myeloid leukemia (AML).

Researchers have now come up with a novel molecule that may inhibit the progression of recurring acute myeloid leukemia (AML). Scientists at the University of Massachusetts Medical School and the University of Virginia have been collaborating, and they report on a new compound designed to specifically target a cancer-causing transcription factor.1 Until now, this was thought to be an undruggable target. The researchers report in Science that this strategy may be used to design other novel molecules that can specifically inhibit cancer-causing transcription factors.   

Transcription factors are single- or multi-protein complexes. They regulate transcription of DNA into messenger RNA and gene expression by binding to regions on the genome. Mutations in transcription factors can result in altered gene expression programs that promote cancer. Although these aberrant transcription factors are promising targets for new therapeutics, the complexity of interrupting very specific protein-to-protein interactions has been difficult to accomplish.

Study co-author Lucio Castilla, PhD, who is an associate professor of molecular, cell, and cancer biology at the University Massachusetts Medical School, Worcester, Massachusetts, said inhibitors so far have targeted an enzyme or a receptor. He said there aren't a lot of good examples of transcription factor inhibitors in clinical trials. However, he said his team has used its 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.  

AML patients with an inversion on chromosome 16, also known as inv(16), typically respond to initial chemotherapy treatment; however, recurrences are likely in a fraction of cases. Leukemia in these patients is caused by a small reversal of the DNA sequence on chromosome 16 that combines a gene which controls the production of blood cells and one involved in muscle physiology.

The researchers report that in AML cells with inv(16), the core-binding factor subunit beta (CBFB) gene is fused with the smooth muscle myosin heavy chain (SMMHC) gene. It is believed that the activity of the CBFB-SMMHC fusion protein causes leukemia. The researchers screened a library of small molecules and found that the molecule AI-4-57 inhibited the binding of runt-related transcription factors (RUNX) and CBFB-SMMHC. However, the activity of this molecule was not enough to have a therapeutic effect.

To overcome this problem, they modify the initial compound to specifically target only the mutant transcription factor (CBFB-SMMHC) while leaving the normal one (CBFB) being produced by the other copy of chromosome 16 free to do its job of regulating blood cell production. Subsequently, the researchers were able to develop a bivalent version of the initially screened compound (AI-4-57). After further refinement, the new drug AI-10-49 prolonged the survival rate of mice with inv(16) AML, and was successful in treating in vitro leukemia lines taken from patients.

Angela Koehler, PhD, who is an assistant professor of biological engineering at the Massachusetts Institute of Technology in Boston, wrote in a review accompanying the article that the polyvalent strategy may serve as a template for new drug discovery efforts focused on selective modulation of aberrant fusion proteins arriving from chromosomal translocation events.