indazole-based privileged ligands in polypharmacology: unlocking the 'undruggable' membrane transporter landscape

Membrane transporters are cellular components that oversee maintaining cellular homeostasis, drug absorption, and multidrug resistance. however, the structural complexity and dynamic conformational states of such multilayered entities, coupled with the absence of well-defined binding pockets, have rendered many of them undruggable. indazole-based privileged ligands emerged as drug-discovery candidates, characterized by their unique capability to target multiple proteins and use poly-pharmacological mechanisms to help modulate transporter function, such as p-glycoprotein (p-gp) in combating multidrug resistance in cancer. this review will thoroughly discuss indazole-containing ligands targeting membrane transporters, emphasizing their potential benefit in overcoming drug resistance, enhancing drug delivery, and treating transporter-mediated diseases. the key examples of indazole derivatives and their distinct binding modes and highlights of advances in computational and experimental approaches were discussed to optimize their selectivity and efficacy was also reviewed. finally, some strategies were proposed for leveraging indazole-based scaffolds in rational drug design to tackle the un-druggability of membrane transporters.