A protein domain may be critical to helping patients fighting acute myeloid leukemia (AML) avoid a relapse. Researchers at Rice University
, working with colleagues at Baylor College of Medicine and the University of Texas MD Anderson Cancer Center, have developed a small molecule that could deliver a “one-two punch” to proteins that resist chemotherapy in patients with AML.
Called STAT3, the protein interferes with chemotherapy by halting the death of cancerous cells and enabling them to grow. The molecule discovered at Rice finds and then attacks a previously unknown binding site on STAT3, disrupting its disease-promoting properties. The work led by Rice chemist Zachary Ball, Baylor pediatrician Michele Redell and MD Anderson oncologist David Tweardy appears in the journal Angewandte Chemie and is reported in Bioscience Technology
An earlier discovery by Ball’s lab led to the discovery and exploitation of this new drug target. That discovery enabled researchers to identify, on a molecular level, the target of action for drug molecules by using rhodium-based inorganic complexes. The complexes recognize specific folds in a protein chain and catalyze minute changes in those sequences, thus forming a “tag” for later analysis.
The STAT3 protein (“signal transducer and activator of transcription 3″) is a suspected culprit in the relapse of nearly 40 percent of children who have AML. The new proximity-driven rhodium(II) catalyst known as MM-206 seeks and modifies an inhibitor-binding site on the protein and delivers the inhibitor, naphthalene sulfonamide, to the modified site.
According to Ball, “This is the confluence of two ideas we’ve been working on around what you can do with conjugates linked to rhodium.”
Redell, who is also part of the leukemia and lymphoma teams at Texas Children’s Hospital, added, “We know that increased activity of STAT3 in AML and other cancers helps the cancer cells survive chemotherapy, so any new strategy we can develop to stop that process could mean real benefit for our patients.”
Ball explained that STAT3 has been a target for scientists trying to shut down cancer cells, saying, ”STAT fits in the broad category of what are called ‘undruggable protein-protein interactions.’ There’s a large surface area with weak interactions for which we have typically failed to find good drugs.”
Prior research revolved around only one region of STAT3, its SH2 domain, with limited success. Ball added, “There’s no evidence people have tried to go after the coiled coil as a drug target. Our main advance, from a medicinal perspective, is that this compound also works in a mouse model. All the other compounds worked in cells, but in mice, they weren’t potent enough or stable enough. The discovery raises new questions about STAT3 biology and points the way to future anti-cancer approaches, including combination therapies of coiled-coil STAT3 inhibitors in tandem with other agents.”