Abstract LB-2: Structure-based design of G-quadruplex ligands leads to enhanced potency against pancreatic cancer cells

Abstract

Abstract Certain small molecules can sequester the single-stranded overhang of human telomeric DNA into higher-order quadruplex structures. Such quadruplex-ligand complexes interfere with telomerase activity and inhibit its ability to maintain telomere integrity in many cancer cell types. This approach to selectivity interfering with cancer cell viability has been demonstrated for several classes of quadruplex-binding molecules in cells and in xenograft experiments. We have previously described a series of tetra-substituted naphthalene diimide (ND) compounds with high affinity for human telomeric quadruplex DNA. These also have high potency for growth inhibition in a panel of cancer cell lines, concomitant with telomerase inhibition. Those compounds with N-methyl-piperazine (NMP) end-groups have shown exceptional potency in a pancreatic cancer cell line panel, with the lead compound having typical IC50 values of 100-200 nM. It has significant anti-tumor activity in a pancreatic cancer xenograft model, with a 50% reduction in tumor volume on ip administration, along with inhibition of telomerase activity. We report here a structure-based design study in which the four positive charges of the tetra-NMP compound have been modulated by substituting NMP groups on two of the four side-arms of the ND core with more weakly basic groups, in order to improve drug-like features. A diminution in the highly cationic nature of these ND compounds may improve cellular uptake and tumor distribution properties, while retaining quadruplex affinity. The morpholine group has been used because it is less basic than the NMP group. We hypothesized that the presence of four NMP groups is non-essential in order to retain effective quadruplex binding, since the morpholine group is of equivalent size and so could be bound in the same way. Three co-crystals structures of NMP and morpholino-containing ND compounds with a human telomeric quadruplex have been determined. These show that the morpholino group binds in quadruplex grooves in a closely-similar manner to the NMP group and has the same hydrogen-bonding. Accordingly, several hybrid morpholino-NMP ND compounds have been synthesized and shown high quadruplex affinity, exceptional potency in selectively inhibiting growth in pancreatic cancer cell lines, with IC50 values of <10 nM, together with potent telomerase inhibition in these cells. Lead compounds from this study are currently being taken into further in vivo evaluation, with a view to identifying a compound suitable for pre-clinical development. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-2. doi:1538-7445.AM2012-LB-2