Pipeline Project A: Synthesis of Novel dG-Analogs & Their Effects on Telomerase and Proliferation of Malignant Glioma Cells
Co-Investigators
Jose Rivera, Ph.D., Assistant Professor, Department of Chemistry, University of Puerto Rico at Rio Piedras, Rio Piedras, Puerto Rico
Seiji Kondo, M.D., Ph.D., Associate Professor, Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, Texas
Telomerase, a ribonucleoprotein, is a promising candidate for targeted therapy of malignant gliomas. It is because the vast majority of malignant gliomas express telomerase, while normal brain tissues do not express the activity. Moreover, patients with malignant gliomas lacking telomerase have better survival than those with telomerase-positive. These observations indicate a therapeutic opportunity on telomerase-positive malignant gliomas by inhibiting telomerase.
Telomerase is an enzyme with reverse-transcriptase activity responsible for maintenance of telomeric repeats onto the 3’-end of chromosomes. Most of human telomeric DNA is double-stranded and contains (TTAGGG/CCCTAA)n repeats, except for the extreme terminal part involving a G-rich 3’overhang. This sequence adopts an intramolecular G-quadruplex structure that blocks the catalytic reaction of telomerase. Therefore, agents that directly bind to the telomeres and stabilize G-quadruplexes have the potential to inhibit telomerase activity and disrupt telomere structures. To date, several G-quadruplex interacting agents are shown to exhibit the in vitro and in vivo anti-tumor effect to some extent. To pursue the development of more potent anti-tumor agents, we need to explore more selective and stable G-quadruplex interacting agents.
To develop novel small molecules for the treatment of malignant gliomas, we propose to establish the feasibility of using novel 2’-deoxyguanosine (dG) analogues to create stable G-quadruplexes. Our hypothesis is that increasing the number of desolvated hydrogen H-bonds holding G-quadruplexes together will stabilize their secondary structure leading to inhibition of telomerase. We will synthesize one family of dG-analogs: biaryl-guanosines to test our hypothesis. The rationale for these studies is that G-quadruplexes of increased stability will show an increased inhibition of telomerase activity by disrupting telomere structures.
Our expectations are that, at the conclusion of this research, we will have a more complete understanding on the role of H-bonding in the stability of G-quadruplexes and would have identified novel G-analogs that exhibit anti-tumor effect on malignant glioma cells. Confirmation of our hypotheses will open the door to novel approaches to the development of potentially new treatments for cancer including malignant gliomas.
Specific Aims
- Synthesize and characterize one family of dG-analogs having carefully positioned functional groups capable of increasing potential H-bonding sites relative to dG
- Investigate the ability of such compounds to inhibit the proliferation of malignant glioma cells by inhibiting telomerase and disrupting telomeres