Center for Molecular Innovation and Drug Discovery

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Dr. Karl Scheidt’s Research Featured on Northwestern Now News Article

NORTHWESTERN NOW

“Chemists inhibit a critical gear of cell immortality”

By Megan Fellman

March 3, 2020

The article refers to Targeted Covalent Inhibition of Telomerase published by the journal ACS Chemical Biology. This was a recent publication by Rick C. Betori, Yue Liu, Rama K. MishraScott B. Cohen, Stephen J. Kron, and Karl Scheidt.

“Telomerase is the primary enzyme that allows cancer cells to live forever,” said Karl A. Scheidt, who led the research. “We want to short-circuit this immortality. Now we have designed a first-of-its-kind small molecule that irreversibly binds to telomerase, shutting down its activity. This mechanism offers a new pathway for treating cancer and understanding cellular aging.”

“NU-1 inhibits telomerase unlike anything that came before it,” Scheidt said. “It does this by forming a covalent bond. Another advantage of NU-1 is that its molecular structure should enable scientists to add cargo, such as a therapeutic.”

For the full article by Northwestern Now, visit their webpage here: https://news.northwestern.edu/stories/2020/03/chemists-inhibit-a-critical-gear-of-cell-immortality/.

CMIDD/ChemCore Joins the Chemistry of Life Processes Institute to Celebrate 10 Years of Transformative Science

On October 24, 2019, the Center for Molecular Innovation and Drug Discovery/ChemCore joined the Chemistry of Life Processes Institute (CLP) in celebrating the 10th year anniversary. CLP’s Director, Dr. Tom O’Halloran, introduced the recognition of core and center technical and administrative personnel. Ms. Terri Fraterrigo (Director of Operations and Outreach, CMIDD) then introduced each member of CMIDD/ChemCore.

To learn more about the event, please click here to visit CLP’s website.

Congratulations to Dr. Gary Schiltz (Deputy Director, CMIDD) and Ms. Terri Fraterrigo for celebrating their ten years with CMIDD!

L to R: Mykieu Pham; Atul Jain; Terri Fraterrigo; Purav Vagadia, MS; Cynthia Martin

Congratulations to CMIDD Postdocs on New Positions

July 29, 2019

Congratulations to our Postdoctoral Fellows Dr. Corinne Ley and Dr. Iredia Iyamu on their new positions after completing appointments with CMIDD at Northwestern University!

Dr. Corinne Ley is currently a Scientist in Research Chemistry at Neurocrine. Her primary role is to develop novel anticholinergic drugs for treatment of dystonia, focusing on identifying key pharmacophoric points of current structures and aim to improve the selectivity, metabolism, and brain penetration.

Dr. Iredia Iyamu is currently a Post-Doctoral Research Associate under the direction of Dr. Rong Huang in the Purdue University College of Pharmacy Institute of Drug Discovery.

L to R: Iredia Iyamu, PhD; Javier Izquierdo-Ferrer, PhD; Atul Jain, PhD; Purav Vagadia, MS; Corinne Ley, PhD; Kristen Stoltz, PhD

Feinberg School of Medicine’s Research Day

On April 4, 2019, members from the CMIDD Medicinal Chemistry team were selected to present at Northwestern University Feinberg School of Medicine’s 15th Annual Lewis Landsberg Research Day at the Robert H. Lurie Medical Research Center Hughes Auditorium and Patrick G. and Shirley W. Ryan Family Atrium and Northwestern Memorial Hospital’s Feinberg Pavilion.

It was an opportunity to present scientific posters on each of their individual projects, showcasing their recent progress and key medicinal chemistry findings (both in vivo and in vitro), in addition to networking (and competing) with peers.

 

L to R: Iredia Iyamu, PhD (Postdoctoral Fellow, CMIDD), Corinne Ley, PhD (Postdoctoral Fellow, CMIDD), Purav Vagadia, MS (Research Chemist, CMIDD).

 


To learn more about Research Day, please visit: https://www.feinberg.northwestern.edu/research/about/research_day/poster-competition/index.html.

ChemCore Receives Highly Performing Core Award Certificate

On February 8, 2019, ChemCore received the Highly Performing Core Award Certificate, presented by the Office for Research. Congratulations to the ChemCore staff for their distinguished achievement 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.

L to R: Dr. Philip Hockberger (Associate Vice President for Research; Associate Professor, Physiology), Mykieu Pham (Administrative Assistant, CMIDD and ChemCore), Dr. Kristen Stoltz (Medicinal Chemist, CMIDD and ChemCore), Terri Fraterrigo (Director of Operations & Outreach, CMIDD; Operations Director, ChemCore), Jay Walsh (Vice President for Research).

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.