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Targeting the CXCR4 receptor to Treat Acute Myeloid Leukemia (AML)

NU collaborators from the Center for Molecular Innovation and Drug Discovery (CMIDD), the Robert H. Lurie Comprehensive Cancer Center (RHLCCC), and the Feinberg School of Medicine (FSM), have received funding from the National Cancer Institute (NCI) to develop compounds that may lead to an entirely new treatment for Acute Myeloid Leukemia (AML).

This grant, which will provide $1.58 million over the next three years, will support medicinal chemistry, molecular modeling, and biological testing to optimize small molecule CXCR4-receptor antagonists and agonists. This receptor is known to play a critical role in myriad diseases including cancer, HIV infectivity, and inflammation.

Although the CXCR4 receptor has been widely studied, researchers have been unable to identify small molecule agonists of the receptor, which has made it difficult to fully examine its role in fundamental biological processes. 

However, by harnessing new in silico techniques, Dr. Rama Mishra, CMIDD Cheminformatics Specialist, was able to identify a number of compounds that appeared to bind the receptor. Subsequent in vitro screenings completed by Dr. Richard Miller, Professor of Pharmacology, confirmed an unprecedented finding that many of these compounds acted as agonists towards CXCR4 and that these agonists actually increased the sensitivity of AML cells to drug therapy.

“We have developed an entirely new class of CXCR4 modulators. We expect that these compounds will be very valuable as molecular probes to better understand CXCR4 pharmacology and ultimately, may lead to new advances in therapeutics for AML and other cancers,” said Dr. Gary Schiltz, Assistant Research Professor in CMIDD and PI of the multi-investigator grant. “This is an excellent example of how collaborators with different expertise can carry out truly innovative research.”

With these funds, Dr. Schiltz (CMIDD) will coordinate research efforts with co-PIs Drs. Leonidas Platanias (RHLCCC) and Richard Miller (FSM) to more fully study the biological effects of CXCR4 antagonists and agonists, create more potent and effective compounds, and ultimately develop the basis for an entirely new way to treat AML.

CMIDD Receives Funding to Develop Anti-Metastatic Therapeutics

The Center for Molecular Innovation and Drug Discovery (CMIDD) has received a three-year, $1 million grant from the National Cancer Institute (NCI) to discover effective therapeutic treatment against metastatic prostate cancer.

More than 80% of cancer-related deaths stem from the formation of metastases, incurable secondary tumor growths that spread from their original cancer sites. However, effective anti-metastatic treatments are virtually non-existent due to a lack of potent and selective molecules to target metastasis regulators.

Under the direction of Dr. Karl Scheidt, PI, Director of CMIDD and Professor of Chemistry and Pharmacology, CMIDD researchers will collaborate with the OHSU Knight Cancer Institute to study the MAP2K4 protein, which they identified as a critical mediator of metastasis in prostate cancer.

This project now gives us an unprecedented opportunity to develop new therapy designed to inhibit human prostate cancer cell movement in humans,” says Dr. Raymond Bergan, Associate Director of the Knight Cancer Institute and lead project collaborator with the Center.

This NCI grant will support high throughput screening, medicinal and synthetic chemistry, and biological analysis research to develop first generation anti-metastatic agents for prostate cancer treatment.

CMIDD Collaborative Research Featured on Journal of Medicinal Chemistry August Cover

Magazine Cover

On the cover (right): Dock pose of a first-in-class small molecule antagonist of activin in the novel designed pocket of activin A.(Zhu, J.; et al. J. Med. Chem. 2015,58, 5637–5648)

Activin is a protein associated with several disease conditions, including cancer-related cachexia, preterm labor with delivery, and osteoporosis. Targeting activin and its related signaling pathways with small molecules is one of the goals of the research collaboration between CMIDD/ChemCore and the laboratory of Dr. Teresa Woodruff, Thomas J. Watkins Memorial Professor of Obstetrics and Gynecology, Feinberg School of Medicine.  This work, featured in August’s Journal of Medicinal Chemistry, serves as a starting point for developing a lead compound as a promising therapeutic approach to activin-mediated diseases. The virtual high-throughput screening work featured in this paper was completed by ChemCore’s Cheminformatics Specialist, Dr. Rama Mishra

Read the full coverage: Virtual High-Throughput Screening To Identify Novel Activin Antagonists »

Related Links:

ChemCore

Teresa K. Woodruff Lab

Five H Foundation Pilot Project Award Recipients Announced

CMIDD is happy to announce that through a generous donation from the H Foundation, five investigators have been provided with awards for new, cancer-relevant pilot projects that require the use of the High Throughput Analysis Laboratory and ChemCore.

Both of these cores reside under CMIDD, representing the chemical and biological arms of the Center. The HTAL allows investigators to screen large libraries of compounds to identifiy bioactive relationships. ChemCore offers medicinal and synthetic chemistry, cheminformatics and molecular modeling, and small molecule purification services.

The five awardees are:

  • Navdeep Chandel, PhD, Professor of Medicine, Identifying novel regulators of HIF-1α protein stabilization using a small molecule library screen

Identifying novel regulators of HIF-1α protein stabilization using a small molecule library screen – See more at: http://cancer.northwestern.edu/news/HFPilot2015#sthash.e4yvQ2Gk.dpuf

  • John Crispino, PhD, Professor of Medicine, Identification of novel DYRK1A inhibitors for treatment of pre-B cell and T-cell acute lymphoblastic leukemia
  • Tomoko Hayashida, MD, PhD, Research Associate Professor of Pediatrics, Development of an inhibitor specific to the gamma isoform of PI3K, a novel target for cancer treatment
  • Brian Mitchell, PhD, Assistant Professor of Cell and Molecular Biology, Characterization of a novel small molecule microtubule inhibitor
  • Alexander Statsyuk, PhD, Assistant Professor of Chemistry, Transforming the Future: Targeting the Ubiquitin System to Treat Ewing’s Sarcoma

Read the full coverage: Five Recipients Announced from Medicine, Pediatrics, Chemistry, and Cell & Molecular Biology Departments »

Related Links:

ChemCore

H Foundation

Dr. Karl Scheidt Featured on NBC5 Chicago Autism Treatment Story

CMIDD has truncated NBC5 Chicago’s original article and republished it below. For the full article and video, written and published by NBC5 Chicago on May 18, 2015, visit their webpage here: http://www.nbcchicago.com/investigations/Chicago-Woman-Offers-Controversial-Miracle-Treatment-for-Autism-304056871.html

KAS_NBC

From her home base in Puerta Vallarta, Mexico, Chicago native Kerri Rivera counsels parents of children with autism on a “miracle treatment” that she says can rid their children of the curse of the dreaded disease.

Rivera’s solution — “CD,” as she calls it — is part of a larger protocol that includes a strict diet and advisories for parents to watch for the purging of “parasites” from their children. The chlorine dioxide solution is also known as MMS for “Miracle Mineral Solution,” as Rivera’s colleague Jim Humble, founder of the Genesis II Church of Health and Healing, calls it. In online videos, Humble claims to be a billion-year-old god from the Andromeda galaxy. He has insisted in his videos that MMS cures ailments ranging from malaria to cancer.

“It’s an industrial chemical,” said Dr. Karl Scheidt, director of the Center for Molecular Innovation and Drug Discovery at Northwestern University. “I would say it would be incredibly dangerous for anyone to ingest this, much less a child.”

Indeed, the FDA has branded MMS as “dangerous,” warning that it carries the potential for “nausea, severe vomiting or life-threatening drops in blood pressure.” 

Rivera, however, insists her treatments have changed the lives of scores of children. Tens of thousands have bought her book, she says, and, message boards carry the testimonials of parents who insist slimy parasites have been purged from their children.

“We don’t have a single cause of autism that is linked to a virus or a type of germ or parasite,” Dr. Karan Radwan of the University of Chicago said. “I feel terrified about a procedure like this which could harm many kids.” 

Radwan concedes that he hears from desperate parents, who would gladly try any treatment, no matter how extreme, if it has potential to cure their children.

Indeed, Scheidt notes that MMS has never been submitted for clinical trials as is done with mainstream pharmaceuticals.

“You don’t experiment with children” Scheidt said. “Something that’s this potentially dangerous, why risk it?”

Read the full coverage: Chicago Woman Offers Controversial “Miracle Treatment” »

CMIDD Collaborative Resources Featured: Healing Plants Inspire New Compounds for Psychiatric Drugs

This article was originally published in Northwestern University’s News Center on May 11, 2015. Written by Erin Spain and re-printed here.

Scientists look to healers in Nigeria to develop better therapies for mental disorders

EVANSTON, Ill. — Treatments used by traditional healers in Nigeria have inspired scientists at Northwestern University to synthesize four new chemical compounds that could one day lead to better therapies for people with psychiatric disorders.

In a paper published online in the journal Angewandte Chemie International Edition, the scientists detail how they created these natural compounds by completing the first total syntheses of two indole alkaloids — alstonine and serpentine. These alkaloids, found in various plant species used by healers in Nigeria to treat people with conditions such as schizophrenia and bipolar disorder, have antipsychotic properties that have potential to improve mental disorder treatments.

The current drugs used for schizophrenia effectively treat delusions and hallucinations but are only partially effective for cognitive impairment. Early experimental research of these new compounds in animal models shows promise in improving cognitive impairment, the Northwestern scientists said.

“After billions of years of evolution, nature has given us a great starting point for generating new types of molecules that could end up being used as innovative drugs,” said Karl Scheidt, lead author of the paper. “We’ve learned how to make these natural products in the lab and can now evaluate what are the most effective parts of these natural products for potential therapies.”

Scheidt is a professor of chemistry at Northwestern University’s Weinberg College of Arts and Sciences and professor of pharmacology at Northwestern University Feinberg School of Medicine. He collaborated on this study with Dr. Herbert Meltzer, professor in psychiatry and behavioral sciences, pharmacology and physiology at Feinberg. They are both members of Northwestern’s Chemistry of Life Processes Institute (CLP), which helps foster collaboration between schools and lowers the barriers to scientific discovery.

Meltzer, who has spent much of his career researching drug therapies now in use for schizophrenia and bipolar disorder, approached Scheidt about the possibility of creating these compounds. Meltzer’s longtime research goal is to improve treatment outcomes and develop knowledge of brain mechanisms in mental disorders. Scheidt’s expertise is in designing novel methods and strategies for the construction of complex natural products with important biological attributes.

“The synthesis of these alkaloids, which we have now just achieved, was exceedingly difficult,” said Meltzer, second author of the paper and an attending physician at Northwestern Memorial Hospital. “Karl Scheidt’s expertise in the synthesis of natural products was crucial to the success of this project and is the first step in getting a new drug ready for clinical trials.”

Traditional healers boil these special plants and produce an extract that they administer to people with symptoms of mental illness. However, this extract isn’t pure, and it contains other compounds and materials that may not be beneficial to people with mental disorders.

“Nature did not intend this plant to produce an antipsychotic drug on its own,” Meltzer said.

The collaborative work to create the compounds took place in the Center for Molecular Innovation and Drug Discovery (CMIDD) at Northwestern, using high-level purification resources and state-of-the-art research instrumentation and equipment. Scheidt is the director of CMIDD.

Through an efficient and stereo-selective synthesis, Scheidt and his team created four separate but related natural products. Now a template exists to continue making these compounds as needed for future studies and ultimately for use in clinical drug trials.

“We can make multi-gram quantities of any of the compounds we want,” Scheidt said. “We built the assembly line and are now uniquely positioned to explore their potential.”

Meltzer is already using these compounds in animal studies in his lab to better understand how they affect brain biology and chemistry in the schizophrenia disease model. Early results from his lab show that the compounds may increase the ability of other antipsychotic drugs to improve cognitive impairment.

Other study authors are Dr. Ashkaan Younai and Bi-Shun Zeng of Northwestern University. This study was supported the Chemistry of Life Processes Institute at Northwestern in the form of an Innovators Grant and the Weisman Family Foundation.

– See more at: http://www.northwestern.edu/newscenter/stories/2015/05/healing-plants-inspire-new-compounds-for-psychiatric-drugs.html#sthash.XRckRElW.dpuf

Read the full coverage: Northwestern News »

Related Links:

Enantioselective Syntheses of Heteroyohimbine Natural Products: A Unified Approach through Cooperative Catalysis

Healing Plants Inspire New Compounds for Psychiatric Drugs

CMIDD’s Gary Schiltz Receives NUCATS Funding for ALS Research

This is a modified and truncated excerpt from the Northwestern University Clinical and Translation Sciences Institute (NUCATS) news article titled, Next Round of NUCATS Pilot Awardees Aim to Advance Research in Diabetic Wound Healing, Depression, Amyotrophic Lateral Sclerosis and Polycystic Ovary Syndrome.

The NUCATS Institute is pleased to announce the next round of Pilot Program grant awardees that will help advance research in the following areas: diabetic wound healing, depression, amyotrophic lateral sclerosis and polycystic ovary syndrome.

The NUCATS Institute provides rapid, targeted funding to address small, but critical gaps in clinical and translational research work through the Voucher and Pilot Programs. The Voucher Program awards up to $2,500 and the Pilot Program awards up to $10,000. The Voucher Program is accepting applications on an ongoing basis and the Pilot Program has three application deadlines that are repeated annually.

Gary Schiltz, PhD, research assistant professor in the Center for Molecular Innovation and Drug Discovery (CMIDD), is also familiar with NUCATS funding resources. He utilized the NUCATS Voucher Program in July 2014 to develop a novel assay used to screen for new inhibitors that prevent abnormal repeat ribonucleic acid (RNA) from sequestering a protein in a process linked to Amyotrophic Lateral Sclerosis (ALS). He is now taking advantage of the NUCATS Pilot Program to perform expanded compound screening in the CMIDD and to develop additional assays to characterize the functional effects of the new inhibitors. He ultimately plans to carry out medicinal chemistry optimization of the hits to improve their potency, selectivity, and drug-like properties for investigation as potential ALS therapeutics.

To learn more about the success of the Voucher and Pilot Programs, please visit: http://nucats.northwestern.edu/about/newsroom/2014/11/nucats-awards-four-fsm-research-pilot-program-funding and http://nucats.northwestern.edu/about/newsroom/2014/09/announces-four-voucher-program-awards.

Read the full coverage: Next Round of NUCATS Pilot Awardees Aim to Advance Research in Diabetic Wound Healing, Depression, Amyotrophic Lateral Sclerosis and Polycystic Ovary Syndrome »

H Foundation Pilot Project Awards for CMIDD Cores

The Center for Molecular Innovation and Drug Discovery is pleased to share this Project Pilot Award Announcement from the H Foundation.

H Foundation | Pilot Project Awards

High Throughput Screening and Medicinal Chemistry

Release Date:  March 8, 2015                                                                                     

Application Due Date: April 10, 2015

Funding: up to $20,000 per project

Through the generous support of the H Foundation, members of the Basic Sciences Research Division of Northwestern University’s Robert H. Lurie Comprehensive Cancer Centercan apply for a pilot project award to advance translational research projects with cancer relevance. The pilot awards will provide up to $10,000 on behalf of an investigator directly to the High Throughput Analysis Lab or ChemCore for use of facility services. Up to $20,000 is available for projects that use both the HTA Lab and ChemCore.

Award Objectives and Scope

These awards will support use of the HTA Lab or ChemCore facilities to carry out assay development, pilot screening, and/or chemistry projects with translational research objectives relevant to cancer. These must be new research projects, and not extensions of currently funded ones.  Projects initiated with these awards should provide preliminary results for grant applications to external funding agencies for more long-term projects, such as NIH R21, R01 or larger grants.

HTA Lab and ChemCore Services

The HTA Lab supports the design and execution of complex experiments requiring highly parallel assay setup and data acquisition. Examples include the screening of compound libraries to identify molecules that influence key biological processes.  The HTA Lab has strong expertise in biochemical and cell-based assays, and has its own tissue culture capability.  The facility routinely performs automated liquid handling down to nanoliter volumes, and offers data acquisition with a wide range of high throughput fluorescence, luminescence, label-free, and high content image-based detection platforms. HTA Lab scientists adapt existing bench protocols to high throughput screening formats. Visit http://www.cmidd.northwestern.edu/HTAL to learn more about instrumentation and services.

ChemCore has expertise in all aspects of drug discovery chemistry, including medicinal and synthetic chemistry, cheminformatics and molecular modeling, and small molecule purification services. Examples includes hit evaluation and hit-to-lead development chemistry, compound analog synthesis, chemical probe synthesis, virtual screening, and in silico compound docking.  Starting with hits from screening efforts, ChemCore uses its medicinal chemistry expertise to create increasingly drug-like molecules with therapeutic potential. Visit www.cmidd.northwestern.edu/chemcore to learn more about capabilities and services.

Northwestern’s HTA Lab and ChemCore collaborate to discover and optimize compounds that target processes important in cancer.  This createsan integrated system at Northwestern with capabilities spanning target identification, in silico and wet lab screening, hit confirmation, and hit-to-lead optimization. H foundation pilot projects may incorporate a single or multiple components of these services.

Examples of suitable projects include, but are not limited to, the following:

  • Development, optimization, and/or miniaturization of biochemical or cell-based assays to enable a screen; assay validation with selected chemical or biological agents.
  • Large scale screen (thousands of compounds or conditions) with an existing assay that has appropriate throughput and robustness
  • Design and synthesis of hit analogs (hit-to-lead chemistry) to improve potency or other drug-like properties
  • Synthesis of hit analogs with alternative chemical scaffolds to develop new intellectual property and improve development prospects
  • Synthesis of specific tool compounds to probe biological processes

For additional information and application procedure, visit CMIDD’s RFA page here: http://www.cmidd.northwestern.edu/h-foundation-pilot-project-awards

To be considered, send applications to Benette Phillips, Scientific Program Director at the Lurie Cancer Center, email: schallma@northwestern.edu. For questions and further information please contact Benette Phillips. The deadline for applications is April 10, 2015.

Read the full coverage: H Foundation RFA »

Related Links:

Pilot Awards Application Process

ChemCore

Northwestern Faculty Member Receives Spring 2014 CBC HTS Award

The High Throughput Analysis Lab (HTAL) will work with Dr. Bin Zhang, Associate Professor in Medicine-Hematology/Oncology and Microbiology-Immunology, this Spring with funding from the Chicago Biomedical Consortium’s Spring 2014 High Throughput Screening (HTS) Award.

Zhang’s project, titled “Development of Small Molecule CD73 Inhibitors for Cancer Therapy,” was one of two approved for funding in the latest award cycle.

This is the third round of HTS awards offered by the CBC, which are eligible to consortium schools only: Northwestern University, University of Illinois at Chicago, and University of Chicago. A total of 20 awards have been given, ten of which have been in collaboration with NU’s High Throughput Analysis Lab.

If you are faculty at a CBC institution who is interested in working with the HTAL, contact the Lab’s Research Technologist Sara Fernandez Dunne.

Read the full coverage: CBC Announces 2014 Spring Round HTS Awards »