In developing a compound that exhibits activity against a type of acute myeloid leukemia (AML), investigators have shown that transcription factors are, in fact, “druggable.”
The compound, AI-10-49, selectively binds to the mutated transcription factor CBFβ-SMMHC, and this prevents CBFβ-SMMHC from binding to another transcription factor, RUNX1.
In this way, AI-10-49 restores RUNX1 transcriptional activity, which leads to the death of inv(16) AML cells in vitro and in vivo.
“This drug that we’ve developed is . . . targeting a class of proteins that hasn’t been targeted for drug development very much in the past,” said study author John H. Bushweller, PhD, of the University of Virginia Health System in Charlottesville.
“It’s really a new paradigm, a new approach to try to treat these diseases. This class of proteins is very important for determining how much of many other proteins are made, so it’s a unique way of changing the way the cell behaves.”
Dr Bushweller and his colleagues described their work in Science.
The investigators noted that CBFβ-SMMHC is expressed in AML with the chromosome inversion inv(16)(p13q22). And CBFβ-SMMHC outcompetes wild-type CBFβ for binding to RUNX1, thereby deregulating RUNX1 activity in hematopoiesis and inducing AML.
“When you target a mutated protein in a cancer, you would ideally like to inhibit that mutated form of the protein but not affect the normal form of the protein that’s still there,” Dr Bushweller said. “In the case of [AI-10-49], we’ve achieved that.”
He and his colleagues tested AI-10-49 in 11 leukemia cells lines and found that only ME-1 cells were highly sensitive to the treatment. AI-10-49 effectively dissociated RUNX1 from CBFβ-SMMHC in ME-1 cells, with 90% dissociation after 6 hours of treatment.
But the drug had a modest effect on CBFβ-RUNX1 association. It also had negligible activity in normal human bone marrow cells.
The investigators then tested AI-10-49 in a mouse model of inv(16) AML. Control mice (vehicle-treated) succumbed to leukemia in a median of 33.5 days, compared to a median of 61 days for mice that received AI-10-49.
Dr Bushweller and his colleagues did not evaluate toxicity after long-term exposure to AI-10-49, but they found no evidence of toxicity after 7 days of AI-10-49 treatment.
Next, the investigators tested AI-10-49 in 4 primary inv(16) AML cell samples. They saw a reduction in leukemia cell viability when AI-10-49 was administered at 5 μM and 10 μM concentrations. Bivalent AI-10-49 was more potent than monovalent AI-10-47.
The team said these results suggest that direct inhibition of CBFβ-SMMHC may be an effective therapeutic approach for inv(16) AML, and the findings provide support for therapies targeting transcription factors.
