Alpha Omega Alpha Honor Medical Society

2011 Research Abstract

Developing a new class of cancer chemotherapeutics

Investigator: Andrew Zhang, Case Western Reserve University School of Medicine

Mentor: Chris Dealwis, PhD, Case Western Reserve University School of Medicine

Human ribonucleotide reductase (hRR) catalyzes the reduction of ribonucleoside 5’-diphosphates (NDPs) into deoxyribonucleoside 5’-diphosphates (dNDPs), thus providing a balanced and adequate deoxynucleoside triphosphate (dNTP) pool required for DNA replication and repair. Tumors rely heavily on de novo dNTP synthesis and because hRR acts as the rate limiting step in this process, hRR has become an excellent target for anticancer therapy. The activity of hRR is up-regulated by ATP and down-regulated by dATP in an allosteric manner. Using site-directed mutagenesis based on the structure of dATP-induced hexamer, we identified D16 and H2 as two main residues that define the hexamer interface (H-site). Multiple candidate molecules that target the H-site were identified using the combined in silico docking program, Surflex-Dock. We identified four unique lead molecules based on their ability to bind to the large subunit of hRR using fluorescence quenching spectroscopy. We also tested the efficacy of these lead molecules by determining their IC50 values -using cell-based assays in different cancer cell lines: 231 triple negative breast cancer cell line, LN229 glioblastoma cell line, A549 NSCLC cell line, and Panc-1 pancreatic cancer cell line. Compound 1 has the lowest IC50 value of 0.6-2 µM against the Panc-1 cell line. A few of these compounds exhibit synergistic effects with gemcitabine. Our findings may lead to the development of a novel class of inhibitors directed against the H-site of hRR1 that can be used in cancers which have become resistant to gemcitabine.

Updated on July 30, 2012.

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