Center for Molecular Innovation and Drug Discovery

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Disrupting Gene Transcription Elongation to Treat Cancer

By Will Doss

October 19, 2018

Northwestern Medicine scientists have identified compounds that could slow cancer growth by interrupting a gene transcription process, according to a study published in Cell.

Targeting cancer cells with small chains of peptides — known as KL-1 and KL-2 — delayed tumor progression in mouse models by disrupting the super elongation complex (SEC), according to Ali Shilatifard, PhD, the Robert Francis Furchgott Professor, chair of Biochemistry and Molecular Genetics and senior author of the study.

“We demonstrated over 20 years ago that the transcription elongation rate is central for cancer cells to grow, but nobody had been able to control it,” said Shilatifard, also director of the Simpson Querrey Center for Epigenetics and a professor of Pediatrics. “Now we have developed at Northwestern University for the first time chemical tool compounds that can.”

The SEC regulates transcriptional elongation, a key step in gene transcription. Previous studies demonstrated that malfunctions in SEC contribute to a variety of diseases, including many cancers, but targeting cells with a defective complex has proved difficult thus far.

In the current study, Shilatifard collaborated with Gary Schiltz, PhD, research professor of Pharmacology, deputy director of the Center for Molecular Innovation and Drug Discovery (CMIDD) and co-author of the study, to find a molecule that can disrupt the SEC in cancer cells, thereby slowing cancer cell proliferation.

The investigators examined SEC’s crystal structure, pinpointing a weak spot where a large number of proteins interacted with each other. By developing chemical tool compounds that block this interaction, they could disrupt the protein activity and stability of SEC. According to Kaiwei Liang, PhD, postdoctoral research fellow in the Shilatifard laboratory and the lead author of the study, this approach was preferable to other, more global inhibitory strategies.

“We disrupted the protein-protein interaction within SEC instead of inhibiting the pan-kinase activity of CDK9, which exists in other complexes — pan-CDK9 inhibitors result in more side effects,” Liang said.

The scientists then used a large-scale molecular assay, simulating the use of over ten million compounds, before synthesizing the 160 most promising for real-world experimentation. Out of these 160 compounds, two compounds they named KL-1 and KL-2 were found to most effectively inhibit SEC function in both laboratory tests and live mouse models with cancer, who survived significantly longer when treated with the compounds.

“KL-1 and KL-2 are the first class of SEC inhibitors and have been shown to inhibit SEC in multiple biological models,” Liang said. “These SEC inhibitors could be very promising for the treatment of these diseases.”

In addition, cancers caused in part by common mutations in the MYC gene were also sensitive to the inhibitors, suggesting involvement of transcription elongation in MYC-related cancers, according to the study. Further investigation could shed light on both viable therapies and the process of transcription elongation in general.

“This provides us with a platform to regulate the rate of transcription and elongation for the first time in vivo,” Shilatifard said.

Other Northwestern co-authors include Edwin Smith, PhD, research professor of Biochemistry and Molecular Genetics; Rama Mishra, PhD, research assistant professor of Pharmacology and senior cheminformatics specialist at ChemCore; Rintaro Hashizume, MD, PhD, assistant professor of Neurological Surgery and of Biochemistry and Molecular Genetics; Kristen Stoltz, PhD, medicinal chemist at the CMIDD, and Shilatifard laboratory members Ashley Woodfin, bioinformatician; Emily Rendleman, research technician; Stacy Marshall, lab manager; David Murray, research technician; Lu Wang, PhD, postdoctoral research fellow and Patrick Ozark, bioinformatician.

Shilatifard, Schiltz, Smith and Hashizume are members of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.

CMIDD Postdoc Dr. Corinne Ley Receives Multiple Awards

September 7, 2018

CMIDD would like to congratulate our postdoctoral fellow, Dr. Corinne Ley, on receiving multiple awards on her scientific presentation “Targeted Protein Degradation in Castration-Resistant Prostate Cancer.”

 

Center for Molecular Innovation and Drug Discovery Scholar Award

Sigma Aldrich Best Postdoctoral Poster Award

Northwestern University Postdoctoral Forum (NUPF) Current Research and Future Career Symposium 2018 Best Oral Presentation

 

CMIDD & MilliporeSigma’s Colloquium & Scientific Poster Session a Success

September 7, 2018

On August 29, 2018, CMIDD and MilliporeSigma collaborated to present The Chemical Impact on Life Sciences Colloquium & Scientific Poster Session. This event brought together about 70 faculty, students and postdocs from Northwestern University to exchange their scientific knowledge and showcase the impact of chemistry on medicine.

This year’s Keynote “The development of Rapastinel (Formerly GLYX-13); A rapid acting and long-lasting antidepressant and the evolution of a novel molecular platform for elucidating the role of N-methyl-D-aspartate (NMDA) receptors in synaptic plasticity” was presented by Dr. Joseph Moskal, Director of the Falk Center for Molecular Therapeutics, Professor of Biomedical Engineering and Professor of Neurological Surgery at Northwestern University. In addition, Nischita Prasad, Materials Science Research Technology Specialist for North America presented “Nanomaterials for Bio-Enabling Future Diagnostics and Treatment.” 


CMIDD Scholars were selected based on their innovation and merit within the realm of biomedical research, with demonstrated ability to achieve and contribute to the development of new therapeutics through their current research. Each Scholar was awarded $500 for research or travel to a scientific meeting and was honored during a networking luncheon with MilliporeSigma representatives. Additionally, they had the opportunity to present a poster of their research to compete for the Sigma Aldrich Best Poster Awards including up to $100 Visa gift cards. 

L to R: Joseph Stachewicz (MilliporeSigma), Dalton Kim, Dr. Corinne Ley, Kacper Skakuj, Dr. Stephens, Dr. Chirag Shah (MilliporeSigma)

Best Postdoctoral Poster
Dr. Corinne Ley, Center for Molecular Innovation & Drug Discovery

Postdoctoral Runner-up
Dr. Andrew Stephens, Department of Molecular Biosciences

Best Graduate Student Poster
Kacper Skakuj, Department of Chemistry

Graduate Student Runner-up
Dalton Kim, Department of Neurology/Department of Chemistry

Honorable CMIDD Scholars
Dr. Zibo Zhao, Department of Biochemistry and Molecular Genetics
Dr. Indranil Roy, Department of Chemistry
Dr. Peng Li, Department of Chemistry
Ryan Marcum, Department of Molecular Biosciences
Anjali Rao, Department of Molecular Biosciences
Matthew Verosloff, Chemical and Biological Engineering
Ada Kwong, Department of Chemistry
Lee Robison, Department of Chemistry
Yijing Chen, Department of Chemistry


Following the Colloquium was the Scientific Poster Session and networking reception showcasing the research of an elite group of Northwestern graduate students and postdocs. 


On April 24, 2018, CMIDD and MilliporeSigma held the Aldrich Lecture presented by Gunda Georg, PhD from University of Minnesota. Dr. Georg is Director of Minnesota’s Institute for Therapeutics Discovery and Development and Professor and Head of their Department of Medicinal Chemistry. Her presentation was titled “Drug Discovery in Academia: Minnelide for Pancreatic Cancer and BRD inhibitors for Cancer and Male Contraception.”

L to R: Dr. Chirag Shah (MilliporeSigma), Joseph Stachewicz (MilliporeSigma), Dr. Gunda Georg, Dr. Karl Scheidt, Terri Fraterrigo, Dr. David Klick (MilliporeSigma), Dr. Gary Schiltz


We gratefully acknowledge MilliporeSigma for their contributions to the success of The Chemical Impact on Life Sciences & Scientific Poster Session.

This event was part of the Chemical Biology and Drug Discovery Research Cluster.   

Thank you to all who contributed and participated during our annual Colloquium & Scientific Poster Session. We hope to see you next year!

 

CMIDD-designed Compound Shown to Fight Blood Cancer

University research center pursues translational drug discovery, bringing together chemists and biologists from across Northwestern’s campuses

By Roger Anderson, Northwestern University

December 18, 2017

A pathbreaking series of compounds designed and synthesized at Northwestern’s Center for Molecular Innovation and Drug Discovery (CMIDD) has been shown to starve multiple myeloma — a rare form of blood cancer — of its favorite food.

Tumor cells, including those of the largely fatal plasma cell malignancy multiple myeloma, thrive on glucose. In this cancer, the tumor co-opts the GLUT4 protein, a vital glucose transporter, for its own proliferation and survival.

In a series of biological studies using patient samples of multiple myeloma, the CMIDD-designed compounds antagonized the transporter, helping to starve the cancer cells to death. The research was published October 20 in the European Journal of Medicinal Chemistry.

“Inhibiting a glucose transporter would be a new strategy for attacking multiple myeloma,” says Gary Schiltz, CMIDD deputy director, research professor in pharmacology, and a corresponding author on the paper. “Our ability to conduct molecular modeling and computational chemistry to support the design and synthesis of these compounds exemplifies the center’s ability to facilitate the translation of basic scientific discoveries into therapeutic candidates.”

Schiltz is collaborating on the project with Mala Shanmugam, hematology and medical oncology, at Emory University, and Paul Hruz, pediatrics, at Washington University in St. Louis.

After the new compounds were synthesized at CMIDD — a multidisciplinary center with more than 50 Northwestern faculty across both the Evanston and Chicago campuses — they were sent to Shanmugam and Hruz for testing in different biological assays to determine the compound’s ability to antagonize the GLUT4 glucose transporter. The resulting data were used by CMIDD medicinal chemists to design and synthesize additional analogs of the compounds in an effort to optimize their targeting of GLUT4, while limiting effects on other proteins, including those in the GLUT family.

“CMIDD is especially strong in the very early stages of drug discovery, in part because our computational and medicinal chemistry capabilities are both housed within the center,” says Schiltz. That physical proximity allows drug discovery researchers to interact closely as they evaluate the chemistry and modeling while considering a compound’s biological effects.

“One of the benefits of modeling is that it can be done relatively inexpensively and quickly, while making a significant impact” says Schiltz, a medicinal chemist who joined Northwestern seven years ago. “We can quickly generate compounds that act against the target we are interested in, giving us a rapid foothold on the optimization process.”

Rama Mishra, a CMIDD cheminformaticist who applies computer and informational techniques to chemistry, applied his molecular modeling expertise to evaluate the binding of their GLUT4 antagonists to the protein and inform the design of new analogs with improved potency and selectivity for inhibiting GLUT4. This structure-based design approach is a powerful technique in modern medicinal chemistry because it allows for rapid evaluation of potential compounds computationally prior to their synthesis, which is often very labor-intensive.

“Integrating the biological data with the modeling data provides increased confidence that we are able to accurately characterize the binding of our small molecule to the target protein,” says Schiltz, who is also a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.

In coming months, the inter-institutional research group will improve the compound’s potency and eventually evaluate its pharmacogenetics — how a person’s genetic makeup may alter response to the drug.

“Mala has had terrific success so far in using patient samples to show that the compounds are effective at selectively killing the cancerous cells while sparing healthy ones,” Schiltz says. “We’ve also determined that the new compound can work in concert with existing therapies, making the path forward a bit easier and promising.”

The Cheminformatics and Bioinformatics in Drug Discovery Symposium a Success!

Thank you to everyone who joined the Center for our Cheminformatics and Bioinformatics in Drug Discovery Symposium. The event took place on October 25, 2017 and brought together 70 scientists at the Robert H. Lurie Medical Research Center on Northwestern’s Chicago campus for an afternoon of discussion on modern computational, statistics and data-mining approaches to identify new drugs and drug targets. Attendees included faculty, staff and students from Chicago’s universities including Northwestern, University of Chicago, University of Illinois at Chicago, and Loyola.

We especially thank our guest speakers for helping make this event successful. Dr. Louise Showe, Professor of Molecular & Cellular Oncogenesis at The Wistar Institute, has had an inspiring 34-year career in bioinformatics and genetics. She shared with the audience her exciting work on identifying biomarkers in the blood for early detection of lung cancer. Dr. Susan Gregurick, Division Director of Biomedical Technology, Bioinformatics, and Computational Biology at NIGMS-NIH, provided an informative overview of the initiatives and funding mechanisms at NIH for supporting bioinformatics and cheminformatics related research.  Dr. Gregurick also shared the new funding mechanism offered by NIGMS intended to provide sustained research support to investigators. Click here to view Dr. Gregurick’s slide presentation.

Additionally, CMIDD thanks to Northwestern faculty, Dr. Ramana Davuluri, Professor of Preventative Medicine, Health & Bioinformatics and Dr. Rama Mishra, Research Assistant Professor in CMIDD-Cheminformatics, for also presenting their work and especially for spearheading this successful event.

View our event calendar to learn about upcoming CMIDD events.

ChemCore receives 2017 Outstanding Core Facility Award

CMIDD is pleased to announce that ChemCore has received the 2017 Outstanding Core Facility Award, presented by the Office for Research.

The award is given to Northwestern core facilities that place in the top 10% based information provided in 2017 annual reports as well as other considerations pertaining to the operation of facilities during the past year. This is the second consecutive year that ChemCore has been given this award. Congratulations to the ChemCore staff for their outstanding performance and thank you to all our users!

The Office for Research Core Facilities Administration honored ChemCore and other award winning facilities at a special Core Facilities Colloquium and Awards luncheon on September 27, 2017.

L to R: Jian Cao, Associate VP for Research; Jay Walsh, Vice President for Research; Javier Izquierdo-Ferrer, Lurie-CMIDD Translational Research Fellow in Medicinal Chemistry, ChemCore; Gary Schiltz, Director of Chemistry, ChemCore; Purav Vagadia, Medicinal Chemist, ChemCore; Terri Fraterrigo, Director of Operations and Outreach, CMIDD and Operations Manager for ChemCore; Atul Jain, Medicinal Chemist, ChemCore; Andy Ott, Director of Core Facilities, Office for Research; Phil Hockberger, Associate Vice President for Research.

CMIDD’s First Aldrich Lecture and Drug Discovery Poster Session a Success

On April 4, 2017, CMIDD collaborated with MilliporeSigma to present the first Aldrich Lecture and Drug Discovery Poster Session. The event garnered the attendance of 40 students, faculty, and staff from a variety of disciplines such as neurobiology, biomedical engineering, and molecular biosciences from both Chicago and Evanston campuses to engage in dynamic discussions and sharing of research. The event’s keynote speaker, Dr. Dirk Trauner, Professor of Chemistry at New York University, presented a compelling lecture entitled, “Controlling and Mimicking Biological Functions with Synthetic Photoswitches.” Dr. Trauner discussed the advantages and disadvantages of synthetic photoswitches and their potential uses in biology and medicine, in particular with respect to restoring vision, alleviating pain, and fighting cancer. We’d like to thank Dr. Trauner for his special visit to Northwestern and the time spent with our students and faculty. For more information on Dr. Dirk Trauner’s research, click here.

Also a first for CMIDD was the presentation of the Drug Discovery Scholars award. This award was designed by CMIDD to highlight graduate students and postdoctoral fellows who demonstrated ability to achieve and contribute to the field of drug discovery through their current research. Scholars were selected based on their ability to convey their passion, creativity, and leadership within their respective discipline through an application process. On the day of the Aldrich Lecture, Scholars were honored at a networking breakfast with Dr. Trauner and MilliporeSigma representatives; presented with a certificate of acknowledgement; awarded $500 for their research or the cost of attendance at a drug discovery related conference; and presented their research poster at the Drug Discovery Poster Session. Each Scholar was eligible for the Best Poster Award provided by MilliporeSigma. We’d like to acknowledge the winners of the Best Poster Award and all participants, and thank them for their contributions to drug discovery research:

  • Best Postdoctoral Poster: Dr. Marc Morgan, Department of Biochemistry & Molecular Genetics, Feinberg School of Medicine
    • Postdoctoral Runner-up: Dr. Vania Vidimar, Department of Obstetrics & Gynecology, Feinberg School of Medicine
  • Best Graduate Student Poster Winner: Kristine Deibler, Department of Chemistry, Weinberg College of Arts & Sciences
    • Graduate Student Runner-up: Rick Betori, Department of Chemistry, Weinberg College of Arts & Sciences
  • Honorable Drug Discovery Scholars:
    • Dr. Maris Cinelli, Department of Chemistry, Weinberg College of Arts & Sciences
    • Dr. Shahrnaz Kemal, Department of Cell & Molecular Biology, Feinberg School of Medicine
    • Elizabeth Johnson, Department of Chemistry, Weinberg College of Arts & Sciences
    • Stefan Zdraljevic, Department of Molecular Biosciences, Weinberg College of Arts & Sciences
    • Brittany Hopkins, Department of Pharmacology, Feinberg School of Medicine
       

      Thank you to all who contributed to and attended the first Aldrich Lecture and Drug Discovery Poster Session.

      We hope to see you there next year!

ChemCore Receives 2016 Outstanding Core Facility Award

CMIDD is pleased to report that ChemCore has received an outstanding Core Facility Award Office for Research’s 7th Annual Core Facility Awards. Outstanding Core Facilities in 2016 were those that placed in the top 10% of this year’s rankings. Last year, ChemCore was proud to be recognized as an Honorable Mention (top 20% of rankings).

The RHLCC Flow Cytometry Facility and the Center for Translational Imaging (CTI) also received Outstanding Core Facility Awards this year.

Congratulations ChemCore!

Related Links:

ChemCore

 

CMIDD Welcomes New Research Faculty

CMIDD is happy to welcome Dr. Matthew Katcher as a Research Assistant Professor. Matt has a strong background in medicinal chemistry and brings a skillset from both academia and industry. He received his B.A. in Chemistry from Harvard University, after which he worked as a Medicinal Chemist in the oncology and neuroscience teams at Merck Research Laboratories for three years. In 2008 he began his graduate studies in the lab of Dr. Abigail Doyle at Princeton University conducting experimental and computational studies to elucidate the mechanism of nucleophilic fluorination methods used in the lab. Matt then worked as an NIH Fellow in the lab of Dr. Timothy Jamison at MIT, where he investigated the multi-step synthesis of ladder polyether natural products and initiated a project using photochemistry in continuous-flow conditions.

Matt is a valuable addition to the team whose overriding goal is to expand the Center’s relationship with biological investigators in need of medicinal chemistry expertise to translate basic discoveries into new therapeutics. In this role, he will evaluate new potential drug targets and generate proof of concept data that will lead to new external funding and commercialization.

Investigators that are interested in discussing new collaborations, research grant aims for potential projects, or project design should contact the Center at drugdiscovery@northwestern.edu or submit the form below.


 

 

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.”