UROP paper, 2014, Chemistry and BiochemistryUndergraduate Research Opportunities Program, University of Minnesota Dulut

Heikkila, Chaz J.

University of Minnesota Digital Conservancy

Evaluation of the Efficacy of novel HK and GADPH Inhibitors in 
Cancer Cells 
 
Chaz J. Heikkila 
Swenson College of Science and Engineering 
University of Duluth Minnesota 
Heikk089@d.umn.edu 
 
 
Introduction 
 
The rapid, uncontrolled growth of tumor cells is characterized by elevated aerobic glycolysis and 
the repression of oxidative phosphorylation (OXPHOS), known as the Warburg effect
1
. 
Although glycolysis is inefficient in producing ATP when compared to OXPHOS, cancer cells 
preferentially activate glycolysis in order to preserve carbon skeletons for biosynthesis, prevent 
reactive oxygen species (ROS)-induced cell death and sustain growth in hypoxic or acidic 
environments
1
. The metabolic differences between normal and cancerous cells offer therapeutic 
strategies that involve preferentially killing cancer cells by inhibition of glycolytic enzymes. 
Major pharmacological targets of the glycolytic pathway include hexokinase (HK), 
phosphofructokinase (PFK) and glyceraldehyde 3-phosphate dehydrogenase (GADPH). Already, 
HK inhibitory molecules such as 3-bromopyruvate, a pyruvate analog, and lonidamine, an 
indazole carboxylic acid derivative, are undergoing clinical trials for the treatment of various 
types of cancer
1
. As promising enzyme targets for tumorigenesis attenuation, my project 
objective was to synthesize and evaluate the efficacy of novel HK and GADPH inhibitors. 
 
Using organic reaction techniques such as reduction, bromination and base-catalyzed coupling, a 
library of over 30 HK and GADPH inhibitors was established for in vitro kinetic assays. After 
several rounds of structure optimization, our compounds show potent inhibition of GADPH and 
HK and are non-cytotoxic. We are currently increasing the water solubility of our molecules to 
improve cellular uptake for in vivo analysis. Ultimately, the efforts of the past seven months in 
the lab have resulted in potential tumor inhibitors that will soon undergo animal testing by 
trained graduate students. And the research experience has been highly rewarding in itself. 
 
This research has sparked my passion for scientific discovery and clarified potential professional 
goals. From organic synthesis to NMR spectroscopy and in vitro biological analysis, I have 
partaken in various aspects of pharmaceutical design that will be invaluable to future endeavors 
as a clinical pharmacist and post-doctoral fellow. For the first time in my life, I feel a genuine 
sense of ownership and pride in my work that motivates me to achieve long-term goals in 
pharmacological research and education. 
 
Furthermore, this research has developed a personal confidence in my ability to add value to 
research teams and achieve autonomy in my work. Beginning as an undergraduate research 
volunteer, I have progressed to a grant-funded lab technician who now trains and directs new 
volunteers. Overall, I am grateful to be participating at the forefront of cancer therapy discovery 
and excited for the direction my career path is taking as a result of this research. 
 
References 
 
1. Lopez-Lazaro, Miguel. (2008) The Warburg effect: why and how do cancer cells activate 
glycolysis in the presence of oxygen? Anti-Cancer Agents in Medicinal Chemistry 8: 305-
312. 


Evaluation of the Efficacy of novel HK and GADPH Inhibitors in Cancer Cells

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Evaluation of the Efficacy of novel HK and GADPH Inhibitors in Cancer Cells

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