Functional and Structural Polypharmacology of Indazole-based Privileged Ligands to Tackle the Undruggability of Membrane Transporters

Abstract

Despite the significant roles of solute carrier (SLC) and ATP-binding cassette (ABC) transporters in human health and disease, most remain poorly characterized as intrinsic and/or xenobiotic ligands are unknown, rendering them as ‘undruggable’. Polypharmacology, defined as the simultaneous engagement of multiple targets by a single ligand, offers a promising avenue for discovering novel lead compounds addressing these emerging pharmacological challenges – a major focus in contemporary medicinal chemistry. While common structural motifs among phylogenetically diverse proteins have been proposed to underlie polypharmacology through the concept of 'multitarget binding sites', a comprehensive analysis of these functional and structural aspects from a medicinal chemistry perspective has yet to be undertaken. In our study, we synthesized 65 distinct indazole derivatives and evaluated their activity across a broad biological assessment platform encompassing 17 specific and polyspecific SLC and ABC transporters. Notably, ten indazole compounds exhibited cross-target activity against challenging transporter targets associated with neurodegeneration (ABCA1), metabolic reprogramming (MCT4), and cancer multidrug resistance (ABCC10). One lead molecule demonstrated exceptional potency against these assessed targets. Furthermore, molecular blind docking experiments and advanced binding site analyses revealed, for the first time, conserved binding motifs across MCTs, organic anion transporting polypeptides (OATPs), organic cation transporters (OCTs), and ABC transporters, characterized by specific and recurring residues of tyrosine, phenylalanine, serine, and threonine. These findings highlight not only the potential of polypharmacology in drug discovery but also provide insights into the structural underpinnings of ligand binding across membrane transporters.