Abstract B204: Targeting key DNA/RNA heteroduplex of telomerase by small-molecule ligands.

Abstract

Abstract Small molecules can be designed to target the DNA/RNA hybrid (DRH) duplex that forms during the catalytic cycle of telomerase. Formation of this unique heteroduplex, which is typically between 4-11 base pairs long, is a key step in the mechanism of telomerase extension. Small molecules that bind to this duplex may inhibit telomerase by either stabilizing the structure thereby preventing strand dissociation (a key step in the catalytic cycle of telomerase), or by sufficiently distorting the substrate duplex causing misalignment of key catalytic groups. As telomerase is frequently over-expressed in cancer cells, the DRH duplex is a good therapeutic target. Thus we initiated a screening programme initially based on the National Cancer Institute (NCI) compound libraries which provide a high degree of structural diversity. Three novel scaffolds were identified in a Fluorescent Resonance Energy Transfer (FRET) based assay that showed at least a 5°C selective stabilization of the DNA/RNA hybrid duplex at 5μM ligand concentration. Medicinal chemistry modifications were then employed on these scaffolds to generate focused libraries of analogues with drug like properties. In total, 30 molecules were synthesized based on the identified scaffolds and subsequently screened against seven different DNA sequences including telomeric and promoter G-quadruplexes, and DRH sequences. A number of compounds showed selective DNA/RNA hybrid stabilization potential without significant affinity for G-quadruplex or duplex DNA sequences. These ligands provided hybrid DNA/RNA stabilization in the range of 5.2-9.5°C at 1μM ligand concentration. A second generation molecules where amides have been replaced by secondary amines are currently being synthesized to obtain SAR. Selected analogues from both compounds set are currently being evaluated in a variety of biological assays to confirm selective telomerase inhibition, and in cell based experiments to assess their potential as antitumour agents. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B204. Citation Format: Mohammad K. Islam, David E. Thurston, Khondaker M. Rahman. Targeting key DNA/RNA heteroduplex of telomerase by small-molecule ligands. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B204.