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News Article | September 2, 2016
Site: www.biosciencetechnology.com

The National Institute of Mental Health announced a $15.4 million initiative that will bring academia and industry together using induced pluripotent stem cell (iPSC) technology to delve into the cellular underpinnings of schizophrenia and bipolar disorder and identify or develop drugs to treat the illnesses. Hongjun Song, Ph.D. of Johns Hopkins University School of Medicine and Rusty Gage Ph.D., of the Salk Institute for Biological studies, will co-lead the consortium, which is made up of four academic institutes and two industry partners. The two other academic partners are the University of Michigan and Conrad Prebys Center for Chemical Genomics at the Sanford Burnham Prebys Medical Discovery Institute. The industry partners are Janssen Research & Development and Cellular Dynamics International. According to the announcement, one of the major goals of the project will be to improve the quality of iPSC technology, by creating standards and a reliable, scalable, and reproducible test system for quickly screening libraries of drugs that may be effective against the disorders. “There has been a bottleneck in stem cell research,” Song, professor of neurology and neuroscience at Johns Hopkins said in a prepared statement. “Every lab uses different protocols and cells from different patients, so it’s really hard to compare results.  This collaboration gathers the resources needed to create robust, reproducible tests that can be used to develop new drugs for mental health disorders. The research groups hope to take into account a large variety of genetic differences by using iPSCs created from more than 50 patients with bipolar disorder or schizophrenia.  The teams will generate four different types of brain cells using iPCs to see which types of cells are influenced by certain genetic differences and at what stage in development those effects occur. After characteristics of each disease are determined at a cellular level, the industry partners will use the system to help determine or develop drugs that can treat these illnesses. “This exciting new research has great potential to expedite drug discovery by using human cells from individuals who suffer from these devastating illnesses,” Husseini K. Manji, M.D., the global therapeutic area head of neuroscience for Janssen Research & Development said in the statement. “Starting with a deeper understanding of each disorder should enable the biopharmaceutical industry to design drug discovery strategies that are focused on molecular pathology.” The consortium hopes that the large amounts of data produced on the molecular and genetic differences between the two disorders will also provide insights for the study of many other mental illness that share some of the genetic variations as bipolar disorder and schizophrenia. The precompetitive agreement is funded by the National Cooperative Reprogrammed Cell Research Groups, which was created by the NIMH in 2013. Bipolar disorder is characterized by severe shifts in mood, energy, and activity levels, and affects about 5.7 million American adults, according to the National Institute of Mental Health. While there are medications that treat symptoms of schizophrenia, which is a disease that affects about 3.2 million Americans, the underlying causes are still unknown.


News Article | December 12, 2016
Site: www.eurekalert.org

La Jolla, Calif., December 9, 2016 -- Certain type 2 diabetes drugs promote weight loss, but how they do this remains poorly understood. Insight into how these drugs work in the body--and especially the brain--could help create new drugs that effectively control body weight. In an important advance on that front, a new study from Sanford Burnham Prebys Medical Discovery Institute (SBP) shows that these drugs, called glucagon-like peptide-1 receptor agonists (GLP-1RAs), reduce body mass by targeting a different part of the brain than previously thought. "GLP-1RAs cause people to eat less, and their weight loss effects were thought to rely on the hypothalamus, a part of the brain that controls appetite," says Julio Ayala, Ph.D., associate professor at SBP and senior author of the study, published in the journal Diabetes. "There was some evidence to support this notion, but it hadn't been directly tested. In this study, we show that it's not the case--other regions of the brain must be involved in weight loss caused by GLP-1RAs." Though the search for weight loss drugs has been intense, there are very few effective drugs on the market. One GLP-1RA has been recently approved to treat obesity in non-diabetics, but patients generally only lose a small percentage of their body weight. Another drawback of GLP-1RAs is that they are given by injection twice a day, and some studies suggest that they increase the risk of pancreatitis. "Better treatments for obesity would make a huge impact on public health," adds Ayala. "GLP-1RAs are a tool towards that end--if we can understand how they lead to weight loss, we may be able to design drugs that act on just the right parts of the brain, or modify GLP-1RAs to be more effective." GLP-1RAs include liraglutide (brand name Victoza), exenatide (Byetta), and albiglutide (Tanzeum). They mimic the hormone GLP-1, which is normally released from the intestine following a meal. GLP-1 acts on the pancreas to trigger release of insulin and lower blood sugar, on the stomach to slow digestion, and on the brain to reduce food consumption, among other effects. Ayala's team examined whether actions in the hypothalamus were essential for GLP-1RAs to induce weight loss using mice lacking GLP-1 receptors in that region of the brain. In these mice, GLP-1RAs still reduce food intake and lower body mass, indicating that the hypothalamus is not the only part of the brain required for the drugs' effects on weight. "Our findings show that we still have work to do to understand what GLP-1RAs are doing in the brain," commented Ayala. "But we know where to start. We're already looking at their effects on brain regions that are involved in the reward associated with eating, such as the ventral tegmental area and the nucleus accumbens." "Though the idea that the hypothalamus was central to GLP-1RAs' effects on eating had become accepted in the field, in a way it's not surprising that it turns out to be more complicated," Ayala added. "Feeding is a complex behavior that's controlled by a complex organ, so these drugs likely modulate more than just one brain region--they probably impact entire circuits. That's where our research is headed." This research was performed in collaboration with scientists at the University of Pennsylvania, the University of Michigan Health System, and the Lunenfeld-Tanenbaum Research Institute at the University of Toronto. Funding was provided by the National Institutes of Health and the Canadian Institutes of Health Research. About SBP Sanford Burnham Prebys Medical Discovery Institute (SBP) is an independent nonprofit medical research organization that conducts world-class, collaborative, biological research and translates its discoveries for the benefit of patients. SBP focuses its research on cancer, immunity, neurodegeneration, metabolic disorders and rare children's diseases. The Institute invests in talent, technology and partnerships to accelerate the translation of laboratory discoveries that will have the greatest impact on patients. Recognized for its world-class NCI-designated Cancer Center and the Conrad Prebys Center for Chemical Genomics, SBP employs about 1,100 scientists and staff in San Diego (La Jolla), Calif., and Orlando (Lake Nona), Fla. For more information, visit us at SBPdiscovery.org or on Facebook at facebook.com/SBPdiscovery and on Twitter @SBPdiscovery.


News Article | February 15, 2017
Site: www.eurekalert.org

La Jolla, Calif., February 15, 2016 (embargoed until 5:00 A.M. EST) -- Biologists have known for decades that enduring a short period of mild stress makes simple organisms and human cells better able to survive additional stress later in life. Now, scientists at Sanford Burnham Prebys Medical Discovery Institute (SBP) have found that a cellular process called autophagy is critically involved in providing the benefits of temporary stress. The study, published today in Nature Communications, creates new avenues to pursue treatments for neurological disorders such as Huntington's disease. Autophagy is a means of recycling cells' old, broken, or unneeded parts so that their components can be re-used to make new molecules or be burned for energy. The process had previously been linked to longevity, in no small part because of research led by Malene Hansen, Ph.D., associate professor at SBP and senior author of the study. The new results suggest that long life and stress resistance are connected at the cellular level. "We used C. elegans--tiny roundworms used to study fundamental biology--to test the importance of autophagy in becoming stress resistant," says Caroline Kumsta, Ph.D., staff scientist in Hansen's lab and lead author of the study. "They're a great model system because they're transparent, so you can easily observe what goes on inside them, most of their genes and molecular signaling pathways have functional counterparts in humans, and they only live a few weeks, which greatly facilitate measuring their lifespans." Kumsta and colleagues incubated worms at 36 °C, significantly above the temperature they are usually kept at in the laboratory, for one hour. After this short heat exposure--a mild form of stress that improves the organism's survival--autophagy rates increased throughout the worms' tissues. When they exposed these heat-primed worms to another, longer heat shock a few days later, worms that were deficient in autophagy failed to benefit from the initial mild heat shock, as observed in heat-primed worms with intact autophagy. The researchers reasoned that a mild heat stress might also improve the worms' ability to handle another condition that worsens with age--buildup of aggregated proteins, which is stressful for cells. To test this hypothesis, Kumsta used worms that model Huntington's disease, a fatal inherited disorder caused by neuronal proteins that start to stick together into big clumps as patients age, leading to degeneration throughout the brain. Exposing worms that make similar sticky proteins in different tissues to a mild heat shock reduced the number of protein aggregates, suggesting that a limited amount of heat stress can reduce toxic protein aggregation. "Our finding that brief heat exposure helps alleviate protein aggregation is exciting because it could lead to new approaches to slow the advance of neurodegenerative diseases such as Huntington's," says Hansen. "The results may also be relevant to Alzheimer's and Parkinson's, which are similarly caused by clumping-prone proteins." "This research raises many exciting questions," adds Hansen. "For example, how does induction of autophagy by a mild heat stress early on make cells better able to survive heat later--what's the cellular memory? There's a lot to follow up on." "A lot of people ask us if this means they should start going to the sauna or do hot yoga," jokes Kumsta. "That may not be an entirely bad idea--epidemiological studies do indicate that frequent sauna use is associated with longer life. But we have a lot more research to do to figure out whether that has anything to do with the beneficial induction of autophagy by heat stress that we see in C. elegans." Kumsta recently received a promotion from postdoc to staff scientist in recognition of her leadership of this study. Financial support for the study was provided by the American Federation for Aging Research and the National Institutes of Health. Sanford Burnham Prebys Medical Discovery Institute (SBP) is an independent nonprofit medical research organization that conducts world-class, collaborative, biological research and translates its discoveries for the benefit of patients. SBP focuses its research on cancer, immunity, neurodegeneration, metabolic disorders and rare children's diseases. The Institute invests in talent, technology and partnerships to accelerate the translation of laboratory discoveries that will have the greatest impact on patients. Recognized for its world-class NCI-designated Cancer Center and the Conrad Prebys Center for Chemical Genomics, SBP employs about 1,100 scientists and staff in San Diego (La Jolla), Calif., and Orlando (Lake Nona), Fla. For more information, visit us at SBPdiscovery.org or on Facebook at facebook.com/SBPdiscovery and on Twitter @SBPdiscovery.


News Article | December 13, 2016
Site: www.eurekalert.org

La Jolla, Calif., Dec. 13, 2016 -- Scientists at Sanford Burnham Prebys Medical Discovery Institute (SBP) have discovered a molecular cause of hydrocephalus, a common, potentially life-threatening birth defect in which the head is enlarged due to excess fluid surrounding the brain. Because the same molecule is also implicated in Down's syndrome, the finding, published today in the Journal of Neuroscience, may explain the ten-fold increased risk of hydrocephalus in infants born with Down's. "We found that deleting the gene for sorting nexin 27, or SNX27, which plays a major role in the development of Down's syndrome, causes hydrocephalus," said Huaxi Xu, Ph.D., the Jeanne and Gary Herberger Leadership Chair of SBP's Neuroscience and Aging Research Center. "The mechanism we uncovered likely only accounts for a fraction of hydrocephalus cases, but we identified potential non-surgical treatments for these cases that deserve further study." Hydrocephalus affects one or two of every 1,000 births. Some causes of hydrocephalus are known, including several well-characterized brain and skull malformations that block fluid outflow, but it can also arise in the absence of other obvious abnormalities. The condition is treated by surgically inserting a shunt to divert the fluid to another part of the body where it can be absorbed. However, these tubes can become infected, and about half the time, they fail, causing headaches, vomiting, fever, and irritability until the shunt is replaced. The new study followed up on prior results from Xu's lab showing that SNX27, a protein that regulates traffic of other proteins within cells, is found at lower than normal levels in the brains of individuals with Down's syndrome. They also found that inactivating the gene for SNX27 in mice causes learning and memory problems similar to those in Down's. Here, Xu's team looked at overall brain development in mice without SNX27. They observed severe hydrocephalus, with fluid-filled cavities (ventricles) in the brain that were much larger than normal. Examining potential causes, they saw that these mice lacked the cells that normally line the ventricles and circulate fluid in the brain, called ependymal cells. The researchers also determined why ependymal cells aren't generated--without SNX27, brain stem cells generate too much of the active form of a protein called Notch that keeps them from becoming ependymal cells. The active form of Notch is created by an enzyme called gamma-secretase, whose activity is regulated by SNX27. Without SNX27, too much gamma-secretase remains active. "Proper flow of fluid out of the brain isn't just crucial in brain development--it also helps eliminate toxic proteins such as amyloid beta, which causes Alzheimer's," added Xu. "Since we've already shown that lack of SNX27 increases production of amyloid beta, genetic variants that cause lower than normal levels of SNX27 would greatly increase risk for Alzheimer's. This double effect likely explains why Down's syndrome patients' brains exhibit Alzheimer's pathology by adulthood." Wang, Xu, and their collaborators went on to show that giving either a drug that inhibits gamma-secretase to SNX27-deficient mice prevents them from developing hydrocephalus. "Gamma-secretase inhibitors could be a future treatment for cases of hydrocephalus caused by ependymal cell defects," commented Xu. "However, further study is required to determine whether this approach is relevant to humans." This research was performed in collaboration with scientists at Xiamen University in China and the Institute of Molecular and Cell Biology in Singapore. Funding was provided by the National Natural Science Foundation of China, the Thousand Young Talents Program of China, the Fundamental Research Funds for the Chinese Central Universities, the National Institutes of Health, the Alzheimer's Association, the Global Down Syndrome Foundation, the BrightFocus Foundation, and the Cure Alzheimer's Fund. Sanford Burnham Prebys Medical Discovery Institute (SBP) is an independent nonprofit medical research organization that conducts world-class, collaborative, biological research and translates its discoveries for the benefit of patients. SBP focuses its research on cancer, immunity, neurodegeneration, metabolic disorders and rare children's diseases. The Institute invests in talent, technology and partnerships to accelerate the translation of laboratory discoveries that will have the greatest impact on patients. Recognized for its world-class NCI-designated Cancer Center and the Conrad Prebys Center for Chemical Genomics, SBP employs about 1,100 scientists and staff in San Diego (La Jolla), Calif., and Orlando (Lake Nona), Fla. For more information, visit us at SBPdiscovery.org or on Facebook at facebook.com/SBPdiscovery and on Twitter @SBPdiscovery.


Brun S.N.,Sanford Burnham Institute for Medical Research | Brun S.N.,Duke University | Markant S.L.,Sanford Burnham Institute for Medical Research | Markant S.L.,Duke University | And 20 more authors.
Oncogene | Year: 2015

Medulloblastoma (MB) is a highly malignant brain tumor that occurs primarily in children. Although surgery, radiation and high-dose chemotherapy have led to increased survival, many MB patients still die from their disease, and patients who survive suffer severe long-term side effects as a consequence of treatment. Thus, more effective and less toxic therapies for MB are critically important. Development of such therapies depends in part on identification of genes that are necessary for growth and survival of tumor cells. Survivin is an inhibitor of apoptosis protein that regulates cell cycle progression and resistance to apoptosis, is frequently expressed in human MB and when expressed at high levels predicts poor clinical outcome. Therefore, we hypothesized that Survivin may have a critical role in growth and survival of MB cells and that targeting it may enhance MB therapy. Here we show that Survivin is overexpressed in tumors from patched (Ptch) mutant mice, a model of Sonic hedgehog (SHH)-driven MB. Genetic deletion of survivin in Ptch mutant tumor cells significantly inhibits proliferation and causes cell cycle arrest. Treatment with small-molecule antagonists of Survivin impairs proliferation and survival of both murine and human MB cells. Finally, Survivin antagonists impede growth of MB cells in vivo. These studies highlight the importance of Survivin in SHH-driven MB, and suggest that it may represent a novel therapeutic target in patients with this disease. © 2015 Macmillan Publishers Limited.


PubMed | University of Pennsylvania, Baylor College of Medicine, Stanford University, Cedars Sinai Medical Center and 8 more.
Type: Journal Article | Journal: Oncogene | Year: 2015

Medulloblastoma (MB) is a highly malignant brain tumor that occurs primarily in children. Although surgery, radiation and high-dose chemotherapy have led to increased survival, many MB patients still die from their disease, and patients who survive suffer severe long-term side effects as a consequence of treatment. Thus, more effective and less toxic therapies for MB are critically important. Development of such therapies depends in part on identification of genes that are necessary for growth and survival of tumor cells. Survivin is an inhibitor of apoptosis protein that regulates cell cycle progression and resistance to apoptosis, is frequently expressed in human MB and when expressed at high levels predicts poor clinical outcome. Therefore, we hypothesized that Survivin may have a critical role in growth and survival of MB cells and that targeting it may enhance MB therapy. Here we show that Survivin is overexpressed in tumors from patched (Ptch) mutant mice, a model of Sonic hedgehog (SHH)-driven MB. Genetic deletion of survivin in Ptch mutant tumor cells significantly inhibits proliferation and causes cell cycle arrest. Treatment with small-molecule antagonists of Survivin impairs proliferation and survival of both murine and human MB cells. Finally, Survivin antagonists impede growth of MB cells in vivo. These studies highlight the importance of Survivin in SHH-driven MB, and suggest that it may represent a novel therapeutic target in patients with this disease.


News Article | February 27, 2017
Site: www.eurekalert.org

La Jolla, Calif., Feb. 27, 2016 -- Scientists at Sanford Burnham Prebys Medical Discovery Institute (SBP) have identified a new regulator of the innate immune response--the immediate, natural immune response to foreign invaders. The study, published recently in Nature Microbiology, suggests that therapeutics that modulate the regulator--an immune checkpoint--may represent the next generation of antiviral drugs, vaccine adjuvants, cancer immunotherapies, and treatments for autoimmune disease. "We discovered that a protein called K-homology splicing regulatory protein (KHSRP) weakens the immune response to viral RNA," says Sumit Chanda, Ph.D., director of the Immunity and Pathogenesis Program at SBP, and senior author of the study. "Depleting KHSRP improved immune signaling and reduced viral replication in cell culture and in vivo, suggesting that drugs inhibiting the protein may have therapeutic value." The innate immune response is the first line of defense against pathogens--a one-size-fits-all attack on viruses, bacteria, and pretty much anything that looks like an invader. But innate immunity must be carefully regulated. If the response is too slow or too weak, infections can run rampant, and if the trigger is too sensitive or the response is too strong, excessive inflammation or autoimmune diseases can arise. "That's where KHSRP comes in," explains Chanda. "It physically interacts with a protein called retinoic acid-inducible gene I (RIG-I) to apply the brakes to the innate immune response." RIG-I receptors initiate antiviral immunity by detecting viral RNA in the cytoplasm of cells. When they bind viral RNA, they turn on signaling that leads to the production of interferon, a strong inflammatory signal that helps kill viruses, as well as the induction of other antiviral responses. RIG-I receptors also coordinate signaling with other immune factors to modulate the adaptive immune response--the acquired, specialized response that develops after the innate response and provides long-term immunity. "We identified KHSRP by systematically testing every human proteins to identify those that impact RIG-I signaling," says Stephen Soonthornvacharin, a recent Ph.D. graduate from the Chanda lab. "We found about 240 proteins, but we focused on KHSRP because it was the only one of the 240 that was found to inhibit the very early steps of RIG-I signaling." "Molecules that block KHSRP's actions could serve as adjuvants--components that heighten the immune response--to vaccines against influenza or hepatitis C, as antiviral drugs, or even next-generation cancer immunotherapies," Soonthornvacharin adds. "Also, among the 240 RIG-I regulators we identified, 125 appear to activate RIG-I, so finding drugs that inhibit these proteins may be a way to treat autoimmune conditions involving too much interferon, like type 1 diabetes or lupus. Figuring out which ones are promising requires further investigation." "We think KHSRP protects against autoimmunity," adds Chanda. "RIG-I normally recognizes RNA molecules that arise during viral infections, but it can also mistakenly sense RNA present in normal cells. Without KHSRP, the innate immune response could be erroneously turned on when there's no virus. Increasing the activity of KHSRP might therefore be a way to treat autoimmunity." "Next, we plan to figure out more of the details of how KHSRP regulates RIG-I," says Sunnie Yoh, Ph.D., staff scientist in the Chanda lab and a key contributor to the research. "That's the information that will move us in the direction of developing therapies." This research was performed in collaboration with scientists at the Novartis Research Foundation, the Icahn School of Medicine at Mount Sinai, Oregon State University Corvallis, the Paul Ehrlich Institute in Langen, Germany, and the University of California San Francisco. Financial support was provided by the National Institutes of Health and the James B. Pendleton Charitable Trust. Sanford Burnham Prebys Medical Discovery Institute (SBP) is an independent nonprofit medical research organization that conducts world-class, collaborative, biological research and translates its discoveries for the benefit of patients. SBP focuses its research on cancer, immunity, neurodegeneration, metabolic disorders and rare children's diseases. The Institute invests in talent, technology and partnerships to accelerate the translation of laboratory discoveries that will have the greatest impact on patients. Recognized for its world-class NCI-designated Cancer Center and the Conrad Prebys Center for Chemical Genomics, SBP employs about 1,100 scientists and staff in San Diego (La Jolla), Calif., and Orlando (Lake Nona), Fla. For more information, visit us at SBPdiscovery.org or on Facebook at facebook.com/SBPdiscovery and on Twitter @SBPdiscovery.


News Article | December 13, 2016
Site: www.eurekalert.org

La Jolla, Calif., Dec. 13, 2016 - Garth Powis, professor and director of Sanford Burnham Prebys Medical Discovery Institute's (SBP) NCI-designated Cancer Center, has been named a Fellow of the National Academy of Inventors (NAI). Election to NAI Fellow status is a high professional distinction accorded to academic inventors who have demonstrated a prolific spirit of innovation in creating or facilitating outstanding inventions that have made a tangible impact on quality of life, economic development, and the welfare of society. Powis is the Jeanne and Gary Herberger Leadership Chair in Cancer Research at the Institute's Cancer Research Center in La Jolla, CA. Previously he was Professor and Chair, Department of Experimental Therapeutics, Division of Cancer Medicine at the University of Texas MD Anderson Cancer Center in Houston, TX. Powis received his B.Sc. in Biochemistry and Pharmacology from the University of Birmingham, and his D.Phil. in Biochemistry and Pharmacology from Oxford University in the U.K. Powis has been a pioneer in the discovery and translation of novel cancer targets and their small molecule inhibitors as potential cancer therapies. His current research focuses on mechanisms that solid tumors use to adapt and survive in hypoxic environments, escape cell death, form new blood vessels and metastasize. Powis is the author of over 350 peer-reviewed publications and 15 patents, supporting first in class anti-cancer agents, three of which are in clinical trials. They include: PX-12, a thioredoxin inhibitor; PX-866, a phosphatidylinositol-3-kinase inhibitor; and PX-478, an inhibitor of hypoxia inducible factor-1 (HIF-1). He is co-founder of two start-up companies, Prolx Pharmaceuticals, which was acquired by Biomira (now Cascadia), and Phusis Therapeutics. "Dr. Powis exemplifies the innovative and entrepreneurial spirit of faculty and researchers at SBP," said Kristiina Vuori, M.D., Ph.D., president of SBP. "His contributions to cancer research have changed the way cancer treatment has evolved, from systemic chemotherapy to personalized molecularly targeted therapy. On behalf of SBP, I would like to congratulate Dr. Powis for the distinguished honor of being elected as an NAI Fellow." The 175 distinguished academic inventors named today bring the total number of NAI Fellows to 757, representing 229 research universities and governmental and non-profit research institutes. The 2016 Fellows are named inventors on 5,437 issued U.S. patents, bringing the collective patents held by all NAI Fellows to more than 26,000. These academic luminaries have made a significant impact on the economy through innovative discoveries, creating startup companies, and enhancing the culture of academic invention. Included among all NAI Fellows are more than 94 presidents and senior leaders of research universities and non-profit research institutes; 376 members of the three branches of the National Academy of Sciences; 28 inductees of the National Inventors Hall of Fame; 45 recipients of the U.S. National Medal of Technology and Innovation and U.S. National Medal of Science; 28 Nobel Laureates, 215 AAAS Fellows; 132 IEEE Fellows; and 116 Fellows of the American Academy of Arts & Sciences, among other awards and distinctions. Powis will be inducted on April 6, 2017, as part of the Sixth Annual Conference of the National Academy of Inventors at the John F. Kennedy Presidential Library & Museum in Boston, MA. U.S. Commissioner for Patents, Andrew H. Hirshfeld will provide the keynote address for the induction ceremony. In honor of their outstanding accomplishments, Fellows will be presented with a special trophy, medal, and rosette pin. Sanford Burnham Prebys Medical Discovery Institute (SBP) is an independent nonprofit medical research organization that conducts world-class, collaborative, biological research and translates its discoveries for the benefit of patients. SBP focuses its research on cancer, immunity, neurodegeneration, metabolic disorders and rare children's diseases. The Institute invests in talent, technology and partnerships to accelerate the translation of laboratory discoveries that will have the greatest impact on patients. Recognized for its world-class NCI-designated Cancer Center and the Conrad Prebys Center for Chemical Genomics, SBP employs about 1,100 scientists and staff in San Diego (La Jolla), Calif., and Orlando (Lake Nona), Fla. For more information, visit us at SBPdiscovery.org or on Facebook at facebook.com/SBPdiscovery and on Twitter @SBPdiscovery.


Correa R.G.,Sanford Burnham Institute for Medical Research | Khan P.M.,Sanford Burnham Institute for Medical Research | Askari N.,Sanford Burnham Institute for Medical Research | Zhai D.,Sanford Burnham Institute for Medical Research | And 9 more authors.
Chemistry and Biology | Year: 2011

NLR family proteins play important roles in innate immune response. NOD1 (NLRC1) activates various signaling pathways including NF-κB in response to bacterial ligands. Hereditary polymorphisms in the NOD1 gene are associated with asthma, inflammatory bowel disease, and other disorders. Using a high throughput screening (HTS) assay measuring NOD1-induced NF-κB reporter gene activity, followed by multiple downstream counter screens that eliminated compounds impacting other NF-κB effectors, 2-aminobenzimidazole compounds were identified that selectively inhibit NOD1. Mechanistic studies of a prototypical compound, Nodinitib-1 (ML130; CID-1088438), suggest that these small molecules cause conformational changes of NOD1 in vitro and alter NOD1 subcellular targeting in cells. Altogether, this inaugural class of inhibitors provides chemical probes for interrogating mechanisms regulating NOD1 activity and tools for exploring the roles of NOD1 in various infectious and inflammatory diseases. © 2011 Elsevier Ltd. All rights reserved.


News Article | November 3, 2016
Site: www.eurekalert.org

La Jolla, Calif., November 3, 2016 -- An entire class of proteins called transcription factors, which regulate the activity of certain genes by interacting with specific sequences of DNA, has largely been ignored by the pharmaceutical industry because it's difficult to design and screen drugs against them. But a new study from scientists at Sanford Burnham Prebys Medical Discovery Institute suggests that a key group of transcription factors are in fact 'druggable,' including several that could be targeted to treat cancer, metabolic disease, or autoimmune conditions. "We found that at least seven bHLH-PAS proteins have pockets where drugs would fit and remain tightly bound," said Fraydoon Rastinejad, Ph.D., professor in the Integrative Metabolism Program and senior author of the study. "That strongly suggests that all members of the family have similar, but chemically distinct, crevices that could bind drugs. Since these proteins serve as 'master regulators' for controlling whole gene programs, drugs against these targets could have broader effects than traditional ones that block single enzymes." In the new study, published in eLIFE, Rastinejad and his lab first determined the structures of NPAS 1 and NPAS 3 proteins, each in complex with their partner, ARNT, using X-ray crystallography. All three proteins belong to the bHLH-PAS family of transcription factors. NPAS1 and NPAS3 control genes involved in brain and spinal cord development. Rastinejad's team then compared the new structures to those of four other bHLH-PAS proteins, including two they previously solved, hypoxia-inducible factors (HIFs) 1α and 2α. In all seven proteins, they observed two similarly sized and architecturally positioned cavities in which small molecules could fit. Since three more bHLH-PAS transcription factors were known to interact with small molecules, it's safe to assume that these pockets are a common feature of the whole bHLH-PAS family. Although variations in the NPAS1 and NPAS3 genes have been linked to brain disorders including autism, they aren't obvious drug targets because their function is most important in early life. However, modulating the activity of other bHLH-PAS proteins has been proposed to treat several diseases. For example, using drugs to block HIFs, which help cells survive when little oxygen is available, could stop the growth of certain cancers. Altering the function of the clock circadian regulator (CLOCK) and brain and muscle ARNT-like protein 1 (BMAL1), which keep cellular functions synchronized with day-night rhythms, could treat metabolic problems. And the aryl hydrocarbon receptor (AHR), which controls T cell differentiation, is a potential target for drugs to alleviate autoimmune disease. "The fact that bHLH-PAS proteins have ligand-binding pockets insides their architectures suggests they're regulated by small molecules that are naturally found in the body," added Rastinejad. "That means we have a lot left to discover about these transcription factors. We anticipate that this research will spur many investigations to find their native activators and inhibitors and determine how they affect each protein's activity." This research was performed in collaboration with scientists at the Argonne National Laboratory. Funding was provided by the National Institutes of Health and the Department of Defense Congressionally Directed Medical Research Program. Sanford Burnham Prebys Medical Discovery Institute (SBP) is an independent nonprofit medical research organization that conducts world-class, collaborative, biological research and translates its discoveries for the benefit of patients. SBP focuses its research on cancer, immunity, neurodegeneration, metabolic disorders and rare children's diseases. The Institute invests in talent, technology and partnerships to accelerate the translation of laboratory discoveries that will have the greatest impact on patients. Recognized for its world-class NCI-designated Cancer Center and the Conrad Prebys Center for Chemical Genomics, SBP employs about 1,100 scientists and staff in San Diego (La Jolla), Calif., and Orlando (Lake Nona), Fla. For more information, visit us at SBPdiscovery.org or on Facebook at facebook.com/SBPdiscovery and on Twitter @SBPdiscovery.

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