Abstract C171: On- and off-target effects of telomere uncapping G-quadruplex ligands based on pentacyclic acridinium salts

Abstract

Abstract Antitumor properties of the potent G-quadruplex ligand 3,11-difluoro-6,8, 13-trimethyl-8H-quino[4,3,2-kl]acridinium methosulfate (RHPS4) are driven by telomere uncapping events. RHPS4 has good selectivity for quadruplex DNA over duplex DNA as measured by surface plasmon resonance (Kquad 1.1 × 107 M−1); Kdup 3.4 × 105 M−1). In preclinical models of solid tumor xenografts RHPS4 potentiates the activity of camptothecins but good response is dependent on the timing of the drug sequence employed. These experiments teach how an agent of this novel class might be used clinically in combination with chemotherapeutic agents. Although RHPS4 has several ‘drug-like’ qualities (synthetic accessibility, water solubility, cellular uptake), a preliminary toxicological study revealed that the compound is a potent hERG inhibitor (IC50 0.2 M) and has additional receptor interactions, notably with muscarinic M1, M2 and M3 receptors. In an anaesthetized guinea pig cardiac model RHPS4 increased QTcB interval at doses of 5 and 10 mg/kg. Modifications to the peripheral substituents around the pentacyclic core have identified agents with differing on- and off-target effects. Removal of the N(13)-methyl group of RHPS4 to generate an uncharged molecule drastically reduced affinity for the target quadruplex DNA coupled with reduced pharmacological liabilities; increasing the size of the onium group at N(13) from Me to Et reduced affinity for quadruplex DNA (Kquad 0.6 × 106 M−1) and increased hERG inhibition (IC50 0.04 M). After a significant redesign program two isomeric compounds have been identified, 2- and 3-acetylamino-8,13-dimethyl-8H-quino[4,3,2-kl]acridinium iodides with ‘win-win’ profiles - better selectivity for quadruplex DNA and markedly reduced hERG liability (for the 2-acetylamino compound Kquad 2.4 × 107 M−1; Kdup 3.8 × 105 M−1; hERG IC50 3.7 M): for the 3-acetylamino isomer Kquad 2.5 × 107 M−1; Kdup 4.4 × 105 M−1; hERG IC50 18 M). Molecular modeling studies on the favored 3-acetylamino derivative indicate that the pentacyclic core acts as a surrogate K+ stabilizing the G-quadruplex structure with the acetylamino side-chain projecting into a quadruplex groove. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C171.