Compounds that target a novel binding site on STAT3 may one day be used to prevent relapse in acute myeloid leukemia (AML), according to researchers.
STAT3 is known to interfere with chemotherapy and is thought to play a role in many cases of AML relapse.
But preclinical research suggests a compound known as MM-206 can disrupt STAT3’s disease-promoting effects by targeting a previously unknown ligand-binding site on the protein.
Zachary Ball, PhD, of Rice University in Houston, Texas, and his colleagues described this research in Angewandte Chemie.
The team first discovered that the coiled–coil domain (CCD) is a novel ligand-binding site on STAT3. Then, they identified a naphthalene sulfonamide compound, known as C188, that can target CCD and inhibit STAT3.
The researchers tested C188 and compounds synthesized from it—C188-9, C188-9-Rh2, and MM-206—in vitro and in vivo. Only MM-206 proved effective in vivo.
“Our main advance, from a medicinal perspective, is that this compound also works in a mouse model,” Dr Ball said. “All the other compounds worked in cells, but, in mice, they weren’t potent enough or stable enough.”
MM-206 inhibited STAT3 phosphorylation and induced apoptosis in 3 different AML cell lines. The compound also prompted apoptosis in primary tumor cells from pediatric AML patients.
Among mice engrafted with luciferase-expressing MV4-11 AML cells, those that received MM-206 exhibited slower disease progression than untreated mice.
When the mice received 4 weeks of treatment with MM-206, they had significantly fewer tumor cells in their bone marrow and lived significantly longer than control mice (P=0.019 at 10 weeks).
Follow-up studies should lead to improved versions of MM-206, according to Dr Ball.
“The discovery raises new questions about STAT3 biology and points the way to future anticancer approaches,” he said, “including combination therapies of coiled-coil STAT3 inhibitors in tandem with other agents.”
