Improving the Durability of Cancer Treatment

Using chemistry to improve human health

Although scores of highly efficacious cancer drugs have been developed and are at the disposal of physicians, many treatments eventually fail when the patient develops resistance. Understanding the fundamental mechanisms behind why these drugs ultimately fail is necessary for the development of more durable, and potentially curative, therapies. Dr. Daniel Harki, Assistant Professor of Medicinal Chemistry at the University of Minnesota, uses chemistry to gain a greater understanding of the biology of how cancer cells evade drug therapies. Through the design, synthesis, and biophysical characterization of novel small molecules, Harki and coworkers create chemical probes to better characterize those processes in cancer cells that contribute to drug resistance, which contributes basic knowledge that benefits other scientists working in the field. Additionally, their chemical probes also serve as launch points for the development of new cancer drugs, and therefore, they have the potential to contribute to the development of new treatments to benefit cancer patients. Both areas are significantly impactful to human health and are helping to address why some cancers can evade the drugs that are designed to eliminate them.

While organic chemistry is at the core of his research, Dr. Harki also uses techniques of modern biology, genetics, and genomics to probe the biological activities of the compounds they synthesize. Awarded a Hyundai Hope on Wheels grant for his novel insights on childhood cancer research, as well as being named a V Foundation V Scholar for cancer research, Dr. Harki’s team strives to translate their fundamental research to products that can benefit cancer patients. Dr. Harki and his team are developing chemical probes to interrogate processes that cancer cells use to develop cancer drug resistance, and if successful, these probes will also serve as starting points for the development of drugs themselves to boost the durability of existing therapies. In this way, he and his team are able to identify the molecular mechanisms by which cancer cells can develop drug resistance and to develop novel approaches to stop it.

Current research includes:

  • Discovery of APOBEC3 Inhibitors: Dr. Harki and his team collaborate with multiple research groups at the University of Minnesota as well as external collaborators to develop chemical probes and therapeutic molecules that mediate APOBEC3-driven mutational process in cancer. If successful, his research may result in the discovery of drugs that lower the frequency of drug resistance in human cancer.

  • Development of Cancer Stem Cell Inhibitors: Cancer stem cells drive tumor formation and growth in multiple human cancers. Dr. Harki and his team are working on a class of natural products that are toxic to cancer stem cells, but the mechanism by which they exert these useful effects are unknown. Using organic synthesis, he creates tagged natural products to elucidate their molecular targets in cancer stem cells. This research may yield to the discovery of new agents that target cancer stem cells and improve cancer therapy.

  • Chemical Probes of DNA-binding Proteins: Dr. Harki and his team are interested in DNA binding proteins that are deregulated in cancers, such as transcription factors. They have developed a class of DNA-based probes that allow them to bind and release DNA-binding proteins using a non-invasive trigger, light. These new reagents, once fully developed, may yield useful tool compounds for studying deregulated signaling networks in cancer cells.

Bio

As an undergraduate student, Dr. Harki was initially focused on medical training. With a goal of becoming a physician, he was motivated by personal experiences as a volunteer at the local hospital where he frequently interacted with sick kids and those children, suffering from cancer, were particularly memorable to him. He remembers pulling kids around the floor in wagons while also wheeling their IV poles that were used for chemotherapy infusions. At about the same time, Dr. Harki began working in a synthetic organic chemistry laboratory on the total synthesis of a natural product that has cancer inhibitory activity. He was fascinated by the power of organic synthesis and how researchers could affect millions of lives through the discovery of new medicines by crafting molecules that could cure disease. It was the intersection of his motivation to help others and his work as a chemist that brought him to change his trajectory and pursue graduate studies in drug discovery. Dr. Harki has now dedicated his professional career to studying human cancer using chemistry.

Aside from his research, in his free time, Dr. Harki enjoys spending time with his two young children, and playing golf. He is also an avid sports fan; loyal to both the Dodgers and the Steelers, his passion for life is evident not only in the lab, but also during rousing games.

Website: z.umn.edu/harki

Publications

Oxidative reactivities of 2-furylquinolines: Ubiquitous scaffolds in common high-throughput screening libraries

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Synthesis and antileukemic activities of C1-C10 modified parthenolide analogues

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Parthenolide prodrug LC-1 slows growth of intracranial glioma

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Small molecule APOBEC3G DNA cytosine deaminase inhibitors based on a 4-amino-1,2,4-triazole-3-thiol scaffold

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­­­Bicyclic cyclohexenones as inhibitors of ­­­NF-kB signaling

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Small molecule inhibitors of the single-strand DNA cytosine deaminase APOBEC3G

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Awards

Professor of the Semester, University of Minnesota, College of Pharmacy, Class of 2017 - Duluth

V Foundation V Scholar, The V Foundation for Cancer Research, 2012-2014

California Tobacco-Related Disease Research Program, Postdoctoral Fellowship, 2007 - 2009

American Heart Association, Predoctoral Fellowship, 2002 - 2005

Phi Beta Kappa, West Virginia University, 1999

Patents

“Methods and materials for assessing enzyme-nucleic acid complexes”

Harki DA, Kaufmann SH, Perkins AL (2015). U.S. Serial No. 62/186,816, filed June 30, 2015.

“Small molecule inhibitors of APOBEC3G and APOBEC3B”

Harki DA, Harris RS, Perkins AL, Olson ME, Abate-Pella D, Li M (2014). U.S. Serial No. 61/926,751, filed January 14, 2014; converted January 13, 2015 (PCT/US2015/11209).

“Cytosine deaminase modulators for enhancement of DNA transfection”

Harris RS, Harki DA, Perkins-Harki AL, Carpenter MA and Li M (2010). U.S. Serial No. 61/410,482, filed November 5, 2010; converted November 3, 2011 (PCT/US2011/059178).