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SCRIPPS DISCOVERS FALL 2010 Selective Inhibition of BMK1 Suppresses Tumor Growth SC RIPPS DISC OVERS Accelerating Discoveries, Saving Lives A Newsletter for Philanthropists Published Quarterly by The Scripps Research Institute WINTER 2010 | VOL 7 | NO 1 California-Florida RESEARCH UPDATE Scripps Research Scientists Develop Molecular Test Providing a New Pathway for Identifying Obesity and Diabetes Drugs cientists at The Scripps Research Institute The Worm Institute for Research and Medicine have designed a new molecular test that at Scripps Research. Swill allow researchers to look for potential Janda and Amanda Garner, Ph.D., a research drugs targeting a human metabolic enzyme believed associate in his laboratory, described the new to stimulate the appetite and play a role in diabetes. approach—which may also prove useful for The new test, which the scientists call a simple investigating other enzymes involved in a assay, will allow researchers to look through variety of diseases—in an advance, online Early hundreds of thousands of compounds for those that Edition of the journal Angewandte Chemie on have potential to block the action of an enzyme September 15, 2010. known as ghrelin O-acyltransferase (GOAT). If Even though GOAT was only discovered drugs can be found that safely suppress the action recently, in 2008, scientists had speculated for of GOAT, they may help people who have clinical years that it had to exist. After all, its target (ghrelin, problems with appetite, obesity, and diabetes. or the “G” in the acronym GOAT) had been Professor Kim Janda “There hasn’t been a simple screen until now,” known for more than a decade. says Kim D. Janda, Ph.D., a professor in the Ghrelin, a small peptide hormone that is Departments of Chemistry and Immunology mainly produced in the stomach, signals hunger, and Microbial Science, member of The Skaggs typically before meals. Ghrelin has been associated Institute for Chemical Biology, and director of continued on page 2 Team Led by Scripps Research Scientist Inside: 3 . Suppressing Tumor Growth Identifies New Gene for Memory 4 . Donor Profile: The Ellen Browning Scripps Foundation > The Findings Could Shed New Light on Human Learning and 6 . Scientist Profile: Carlos Barbas Neurological and Psychiatric Disorders BACK COVER: A team led by a Scripps Research Institute scientist has for the first time identifie d Smith Appointed Director with American a new gene that is required for memory formation in Drosophila , the common fruit Federation for Aging Research fly. The gene may have similar functions in humans, shedding light on neurological Scripps Florida Grant Supports disorders such as Alzheimer's disease or human learning disabilities. Advanced Technology “This is the first time we have a new memory and learning gene that lies outside Bachovchin Wins California Breast Cancer what has been considered the most fundamental signaling pathway that underlies Research Award learning in the fruit fly,” said Ron Davis, chair of the Scripps Research Department Contact Us of Neuroscience who led the study. “Since many of the learning and memory genes continued on page 2 Obesity/Diabetes, CONTINUED with Prader-Willi syndrome, a common genetic cause of When Janda and Garner set out to develop an assay to childhood obesity in which patients have exceptionall y high monitor GOAT’s activity, they aimed to change this situation. ghrelin levels. The scientists were particularly interested in designing a The biology of ghrelin is quite intricate. For ghrelin to fluorescence-based assay for GOAT. In contrast to radiolabeling impact the body’s metabolism, it must move from the stomach techniques, fluorescence assays are safe, can easily be performed in to the brain, where it acts on neurons. GOAT acts as a “passport” a high-throughput format, and require only a simple light source. checkpoint station for the processing of ‘pro-ghrelin.’ In developing their new approach, the team was inspired “Without GOAT’s modification of ‘pro-ghrelin,’ ghrelin’s by enzyme immunoassay strategies commonly used in biology, entry into the brain, and thus its medicinal implications, are chemistry, and medicine, and by “click chemistry,” a concept nullified,” said Janda. “That’s why GOAT has been coveted as developed at Scripps Research. Because the amount of ghrelin a promising therapeutic target for obesity and diabetes.” modified by GOAT is minute, the scientists also used the principle However, the task of finding drug-like compounds that of multi-turnover signal amplification for accurate detection. target GOAT has been complicated by the fact that the enzyme In the end, the team succeeded in designing and creating is difficult to work with. As a membrane-bound protein, GOAT the new technology—which they call “catalytic assay using cannot easily be purified to homogeneity and has to be suspende d enzyme-linked click chemistry assay” (cat-ELCCA). in a fatty environment. “This new assay technology is both highly sensitive and Most critically, however, no user-friendly high-throughput reproducible,” noted Janda, “making it an excellent assay for screening tests had been developed for this class of enzymes. high-throughput screening.” Current assay technology for targets similar to GOAT rely on Janda and Garner are now further developing the assay so radiolabeling techniques, which are labor-intensive and require that researchers can screen thousands to millions of compounds additional safety precautions. at once against the activity of GOAT. Memory, CONTINUED originally identified in the fruit fly are clearly involved in human pathology of human disease,” Davis said, “but it’s already clear neurological or psychiatric diseases, this discovery may offer that many of these genes will provide important conceptual significant new insights into multiple neurological disorders. information and potential insights into human brain disorders. We’re definitely in the right ballpark.” In addition, there is every reason to believe that their gene The study shows that different products will one day become the target of new drugs to alleles or mutant forms of the enhance cognition. Uncovering this new gene and its signaling gene, known as gilgamesh (gish) , pathway helps bring us that much closer to this goal.” are required for short-term To identify the new gene, Davis and his colleagues used a memory formation in Drosophila novel screen for new memory mutants, looking for lines that olfactory associative learning— showed abnormal learning when only one of two copies of the learning that links a specific gene was mutant. odor with a negative or positive “We used a dominant screen because we realized that reinforcer. behavior such as learning and memory are very sensitive to Because Drosophila learning gene dosage,” Davis said. “That is, the mutation of just one genes are known to be conserved copy of a gene involved in behavior is often sufficient to in higher organisms including produce an abnormality.” humans, they often provide new The formation of new memories occurs, in part, through Professor Ron Davis insights into human brain the activation of molecular signaling pathways within neurons disorders. For example, the that comprise the neural circuitry for learning, and for storing Drosophila gene known as dunce , which Davis helped identify and retrieving those memories. several years ago, provided clues to the genetics of the One of the things that makes the function of gish so devastating psychiatric condition of schizophrenia. Recent interesting, Davis noted, is the fact that it is independent of studies have revealed that the human version of the dunce gene mutations of the rutabaga gene, a Drosophila memory-learning is a susceptibility determinant for schizophrenia. In a similar pathway that is known to be essential for memory formation. way, any new learning gene identified in Drosophila , including The rutabaga mutants convert ATP, the energy chip of cells, gilgamesh , may provide new clues to genes involved in human into cyclic AMP or cAMP, which plays a critical role in neurological or psychiatric disorders. olfactory learning in Drosophila . “We’re still early in the process of making connections “The cAMP pathway is the major signaling pathway used between Drosophila memory and learning genes and the by Drosophila neurons to turn on other enzymes and genes continued on page 3 2 | SCRIPPS DISCOVERS FALL 2010 Selective Inhibition of BMK1 Suppresses Tumor Growth > A Scripps Research study describing a newly developed pharmacological inhibitor is providing detailed insight into how an enzyme that has been implicated in multiple human malignancies regulates a known tumor suppressor. The research may have broad application for treating human cancers. itogen-activated protein kinases (MAPKs) are is inhibited by BMK1. “Previous reports had implicated enzymes that regulate multiple cellular activities, ERK1/2 in the regulation of PML,” says Dr. Lee. “However, Mincluding proliferation and cell survival. Mutations in our study we found that that BMK1 interacts with PML in MAPK signaling pathways have been shown to play a and suppresses its antitumor actions.” To further investigate significant role in many types of cancer. Of the four different the BMK1-PML interaction, the researchers developed a MAPKs that have been identified in mammalian cells, compound called XMD8-92 that was remarkably selective at ERK1/2 and BMK1 exhibit significant structural similarity. inhibiting BMK1. In fact, recent research has shown that some pharmacological Treatment with XMD8-92 blocked tumor cell proliferation
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