#Researchers Find New Clue to Halting Leukemia Relapse A protein domain once considered of little importance may be key to helping patients who are 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 made a small molecule that could deliver a one-two punch to proteins that resist chemotherapy in patients with AML. The protein, called STAT3, interferes with chemotherapy by halting the death of cancerous cells and allowing them to proliferate. The molecule discovered at Rice locates and then attacks a previously unknown binding site on STAT3, disrupting its disease-promoting effects. The new work led by Rice chemist Zachary Ball, Baylor pediatrician Michele Redell and MD Anderson oncologist David Tweardy appears this week in the journal Angewandte Chemie. The discovery and exploitation of this new drug target was made possible by an earlier discovery by Ball lab. That finding enabled researchers to identify, on a molecular level, the target of action for drug molecules by using rhodium-based inorganic complexes that recognize specific folds in a protein chain and catalyze minute changes in those sequences, creating a agfor later analysis. The STAT3 protein it stands for ignal transducer and activator of transcription 3is a suspected factor in the relapse of nearly 40 percent of children with AML. The new proximity-driven rhodium (II) catalyst known as MM-206 finds and modifies an inhibitor-binding site on the protein coiled coil literally protein coils coiled around each other and delivers the inhibitor, naphthalene sulfonamide, to the modified site. his is the confluence of two ideas wee been working on around what you can do linked with conjugates to rhodium, Ball said. e 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, said Redell, who is also part of the leukemia and lymphoma teams at Texas Children Hospital. Ball said STAT3 has been a target for scientists trying to shut down cancer cells. TAT fits in the broad category of what are called ndruggable protein-protein interactions. There a large surface area with weak interactions for which we have failed typically to find good drugs, he said. Previous research revolved around only one region of STAT3, its SH2 domain, with limited success. here no evidence people have tried to go after the coiled coil as a drug target, Ball said, though he noted one paper suggested it might be worth a look. ut they didn follow up on it. ur main advance, from a medicinal perspective, is that this compound also works in a mouse model, he said. ll the other compounds worked in cells, but in mice, they weren potent enough or stable enough. Follow-up studies should lead to improved versions of the complex, Ball said. he discovery raises new questions about STAT3 biology and points the way to future anticancer approaches, including combination therapies of coiled-coil STAT3 inhibitors in tandem with other agents, he said. The National institutes of health, the Robert A. Welch Foundation, the National Science Foundation and the Virginia and L. E. Simmons Family Foundation supported the research a
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