Center for Molecular Innovation and Drug Discovery

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Chetkovich and Schiltz Awarded $1.16 Million to Discover Novel Small Molecule Antidepressants

Northwestern researchers from the Center for Molecular Innovation and Drug Discovery (CMIDD) and the Feinberg School of Medicine (FSM) have received $1.16 million over the next three years from the National Institute of Mental Health (NIMH) to develop novel antidepressant therapies.

Researcher Assistant Professor and CMIDD Director of Chemistry, Gary Schiltz, PhD, and Dane Chetkovich, MD, PhD, Professor of Neurology and Physiology, have designed a screening and drug discovery approach towards a brain channel that could be targeted with small molecule inhibitors.

Dr. Chetkovich previously found that targeting a brain specific auxiliary subunit (TRIP8b) of the HCN channel is sufficient to disrupt HCN channel function and reduce depression-like behaviors in mice. While others have been interested in the HCN channel for new therapies, possible cardiotoxicities associated with targeting the HCN channel directly have precluded its study as a drug target. However, the work by Dr. Chetkovich has shown that by targeting the interaction of the HCN channel with TRIP8b, HCN channel function can be inhibited selectivity in the brain.

“Major depressive disorder (MDD) is a debilitating disease that affects 1 in 5 people worldwide,” said Dr. Schiltz. “Current treatments largely target neurotransmitters in the brain and have remained essentially unchanged for the last 50 years, even though up to half of all sufferers respond inadequately.” 

This funding will support high-throughput screening using in vitro and in silico techniques to identify small molecules targeting this interaction. These hit compounds will then serve as starting points for further medicinal chemistry optimization with the goal of eventually developing new drugs to treat MDD.

“Through this award, we are targeting a novel molecular mechanism that has the potential to benefit a large population of people who urgently need new drug treatment options.”

 

 

 

CMIDD’s 20th Symposium a Success!

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Thank you to everyone who joined the Center for our 20th Annual Drug Discovery Symposium!

This year we had over 80 attendees, two fantastic talks, and a two-hour poster session. We’d like to give a special thank you to Dr. Barbara Slusher, Professor of Neurology, Medicine, Psychiatry and Neuroscience at Johns Hopkins School of Medicine and Director of Johns Hopkins Drug Discovery. Dr. Slusher delivered the keynote, Drug Discovery Goes Back to School, which offered a comprehensive overview of the drug discovery process, particularly in academia, and how the recent growth in academic-industrial partnerships offers a promising platform for therapeutic development. The Center would also like to thank Dr. Alfred George, Chair and Professor of Pharmacology and Director of Pharmacogenomics, for helping us kick-off the symposium with his talk, Drug Discovery Opportunities in the Epileptic Channelopathies.

Crucial to the continuation of this annual event is sponsorship and CMIDD is proud to thank our sponsors of this year’s symposium: Northwestern University Department of Pharmacology, the Driskill Graduate Training Program in Life Sciences at Northwestern University, MilliporeSigma, Fisher Scientific and ThermoFisher Scientific.

Check out our images from this year’s symposium below!

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Congratulations to Paul Lee, MD, PhD, Pediatric Hematology/Oncology Fellow in Dr. John Crispino’s lab and this year’s winner of the Best Poster Given by a Postdoctoral Fellow Award.

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Congratulations to Resham Banga, graduate student in Dr. Chad Mirkin’s lab, and this year’s winner of the Best Poster Given by a Graduate Student Award.

Scheidt Elected Fellow of Royal Society of Chemistry

Karl Scheidt, Director of CMIDD and Professor of Chemistry at Northwestern University, has been awarded the status of Fellow of the Royal Society of Chemistry (RSC). Fellowship of the Royal Society of Chemistry, the United Kingdom’s prestigious professional chemistry association that was incorporated by Royal Charter in 1848 and currently comprises about 50,000 members, recognizes outstanding contributions to the advancement of the chemical sciences. Professor Scheidt is an internationally known organic chemist whose research focuses on the development of new catalytic reactions and the synthesis and application of molecules with important biological and structural attributes.  He is also a Fellow of the American Association for the Advancement of Science (AAAS) and the Alfred P. Sloan Foundation.  The names of recently admitted Royal Society of Chemistry Fellows will be published in The Times of London in the near future.

Announcing the 2015 Silverman CMIDD Research Award Recipients

CMIDD is pleased to collaborate with this year’s awardees:


 

Robert Lamb, John Evans Professor of Molecular and Cellular Biology, Judd A. Marjorie Weinberg College of Arts and Sciences and Investigator, Howard Hughes Medical Institute

PIV5-nucleoprotein structure-based in-silico screening identifies small molecule that inhibits Paramyxovirus replication


 

Teepu Siddique, Les Turner ALS Foundation/Herbert C. Wenske Foundation Professor in Neurology and Professor, Cell and Molecular Biology, Feinberg School of Medicine

Chemical probes based upon 1,3,4-oxadiazoles for affinity capture of target


 

Alfred George, Chair and Magerstadt Professor of Pharmacology, Feinberg School of Medicine, Director, Center for Pharmacogenomics & Milan Mrksich, Henry Wade Rogers Professor of Biomedical Engineering, McCormick School of Engineering, Professor, Chemistry and Cell and Molecular Biology, Judd A. Marjorie Weinberg College of Arts and Sciences

Novel High Throughput Method for Assaying Drug Metabolism


 

About the Silverman CMIDD Research Awards:

These one-year pilot awards provide matching funds for drug discovery related projects that utilize hit-to-lead chemistry or chemical probe development services through CMIDD’s core facility, ChemCore. These awards are made possible by the generous support of Professor Richard Silverman. For more information, please see CMIDD’s Call for Proposals.

 

Interested in a collaboration? Contact us:

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Silverman CMIDD Research Awards Request for Applications

CMIDD is accepting applications for the 2015 Silverman CMIDD Research Awards.  These one-year pilot awards are made possible by the generous support of Professor Richard Silverman.  The awards provide matching funds provide matching funds for hit-to-lead chemistry or chemical probe development.  Click here for the complete RFA. Applications are due by October 29, 2015.

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

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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