GRO26B and GRO29A are G-quartet forming aptamer oligonucleotides that have potent antiproliferative activity against cancer cells in vitro and in vivo. GRO26B has already entered Phase I clinical trials. They are active against a diverse range of tumor types (including lung, prostate, breast, and colon cancers) and are highly selective for malignant cells. The molecular target for these aptamers has been identified as nucleolin, a multifunctional phosphoprotein that is highly expressed in the nucleoli and plasma membrane of cancer cells. It is already well established that high levels of nucleolin expression predict rapid tumor growth rate and poor prognosis in many tumor types. Nucleolin is on the surface of tumor cells and not on the surface of normal cells and we have shown that molecules selectively targeting it enter tumor cells preferentially over normal cells. Therefore nucleolin is a cancer selective target with targeted molecules potentially having lower side effects and toxicity by not entering normal cells. We are undertaking an interdisciplinary approach to the discovery of new small molecules targeting nucleolin. Preliminary data indicate that molecules targeting nucleolin (for example, GRO26B and small molecules that we have already identified using our approach) can also exhibit growth inhibitory activity against cancer cells while not effecting normal cells. We propose that in understanding how GROs and small molecules bind to nucleolin, we can use structure-based drug design to generate new small molecule that have increased efficacy over oligonucleotide-based therapy. Specifically, we need to understand the properties and structures of the GROs and how they are related. Using that information we can examine the complexes with nucleolin to identify specific interactions that are favorable. We will target these regions to screen for new compounds that will be subsequently tested for anticancer effects. The significance of this research is that we could establish a new class of low toxicity small molecule anticancer agents targeted to nucleolin.
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| Bates, Paula J; Laber, Damian A; Miller, Donald M et al. (2009) Discovery and development of the G-rich oligonucleotide AS1411 as a novel treatment for cancer. Exp Mol Pathol 86:151-64 |
| Dailey, Magdalena M; Hait, Chayanendu; Holt, Patrick A et al. (2009) Structure-based drug design: from nucleic acid to membrane protein targets. Exp Mol Pathol 86:141-50 |
