TMC PULSE

t m c » p u l s e | o c t o b e r 2 0 1 5 39 SHORT TAKES 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, inter- feres with chemotherapy by halting the death of cancerous cells and allow- ing 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, M.D., Baylor pediatrician Michele Redell, M.D., and MD Anderson oncologist David Tweardy, M.D., appears in the journal Angewandte Chemie. The discovery and exploitation of this new drug target was made possible by an earlier discovery by Ball's 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 "tag" for later analysis. The STAT3 protein—it stands for "signal transducer and activator of tran- scription 3"—is 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's coiled coil—literally protein coils coiled around each other— and delivers the inhibitor, naphthalene sulfonamide, to the modified site. "This is the confluence of two ideas we've been working on around what you can do with conjugates linked to rhodium," Ball said. "We know that increased activity of STAT3 in AML and other cancers helps the cancer cells survive chemo- therapy, 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's Hospital. Ball said STAT3 has been a tar- get for scientists trying to shut down cancer cells. "STAT fits in the broad cat- egory of what are called 'undruggable protein-protein interactions.' There's a large surface area with weak interac- tions for which we have typically failed to find good drugs," he said. Previous research revolved around only one region of STAT3, its SH2 domain, with limited success. "There's 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. "But they didn't follow up on it. "Our main advance, from a medici- nal perspective, is that this compound also works in a mouse model," he said. "All the other compounds worked in cells, but in mice, they weren't potent enough or stable enough." Follow-up studies should lead to improved versions of the complex, Ball said. "The discovery raises new questions about STAT3 biology and points the way to future anti-cancer approaches, including combination therapies of coiled-coil STAT3 inhibi- tors in tandem with other agents," he said. Co-authors of the paper are Rice graduate students Matthew Minus and Farrukh Vohidov; Baylor College of Medicine postdoctoral associates Wei Liu and Xin Long, researchers Michael Krueger and Mikhail Kolosov, and Alexandra Stevens and Edward Ensure Another 90 Years • Serving Our Community SAN JOSÉ CLINIC The Power of Collaboration Providing the Safety Net Together CHI St. Luke's Health presents Luncheon and panel discussion benefitting San José Clinic Thursday, October 22, 2015 - 11:30 am - 1:00 pm River Oaks Country Club For tickets and more information, visit www.sanjoseclinic.org/FSS2015 This event has been approved for continuing medical education credits: 1 Hour Ethics Credit Featuring a panel of distinguished healthcare executives: Robert C. Robbins, MD with James McDeavitt, MD, George Masi, and Stephen Moore, MD TMCPulse_October2015-FSS.indd 1 9/11/2015 12:00:06 PM Allan Sison, both assistant professors; and MD Anderson Assistant Professor Moses Kasembeli. Tweardy is division head of internal medicine and a profes- sor of infectious diseases and molecular and cellular oncology at MD Anderson. Redell is an associate professor of pediatrics-oncology at Baylor. Ball is an associate professor of chemistry at Rice. 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. — Mike Williams, Rice University T H E P A R K L A N E 1 7 0 1 H E R M A N N D R . | 7 1 3 . 5 2 6 . V I E W 1 7 0 1 H E R M A N N D R . | 7 1 3 . 5 2 6 . V I E W A S K A B O U T O U R G R E A T M O V E I N S P E C I A L S ! • On-Site Storage Included • Assigned Garage Parking • No Water or Garbage Bills • 24hr. Valet & Concierge Service • Pets Accepted • Minutes from Texas Medical Center • Sophisticated Surveillance System • Discount to Texas Medical Center Employees w w w . t h e p a r k l a n e . c o m L U X U R Y A P A R T M E N T S L U X U R Y A P A R T M E N T S

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