The pentacyclic acridinium class of small molecule telomere targeting agents have been shown to stabilise the 3'single-stranded guanine-rich telomeric overhang to fold into a G-quadruplex structure. Stabilisation of the latter is incompatible with an attachment of telomerase and a collection of protective proteins referred to as the shelterin complex to the telomere. G-quadruplex ligands can effectively inhibit the telomere maintenance functions of telomerase while revealing the chromosomal termini to the unwanted attention of DNA repair proteins resulting in telomere specific damage. Potent antitumor properties of the G-quadruplex ligand 3,11-difluoro-6,8,13-trimethyl-8H-quino[4,3,2-kl]acridinium methosulfate (RHPS4) have been reported and shown to be driven by telomere uncapping events. However, in preliminary toxological studies the original lead compound (RHPS4) revealed cardiovascular liabilities related to interactions with hERG receptor (IC50 0.2 uM) as well as additional receptor interactions including muscarinic M1, M2 and M3 and Beta2 adrenergic receptors.

Pharminox have designed and synthesised second generation agents with significantly improved on and off target profiles. Here we describe the modification and optimisation of new telomere targeting agents with an emphasis on their specific effect on telomeres.

Specific bio-molecular assays have been performed on the best compounds of the series, as defined by telomeric DNA binding characteristics and cancer cell activities, “normal” cell selectivities and off target affinities. It was found that all new compounds examined were more potent than RHPS4 as telomere damage inducers. Specifically, at the dose of 0,1 uM, the compounds PMX-000177-761-785 trigger a percentage of TIF-positive cells comparable to that induced by RHPS4 at a 5 fold higher drug concentration. Activation of damage response mainly occurred in replicating cells for the compounds PMX-000177 and -785, suggesting that they can work with a RHPS4-like mechanism of action. As part of a defined screening cascade and candidate target profile, these studies are being used to differentiate between compounds as they progress towards pre-clinical candidate selection status.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A131.