ATP Mimetic Attack on the Nucleotide-Binding Domain to Overcome ABC Transporter Mediated Chemoresistance

Since the problem of transporter-mediated multidrug resistance of tumor cells is becoming increasingly important in cancer therapy, it is necessary to modulate the activity of efflux transporters of the ABC family, among which P-glycoprotein is the best known. We consider the nucleotide binding domain, a universal fragment of these transporters, as a target for the rational design of small molecule compounds capable of preventing ATP-dependent drug efflux. Using various ATP mimetics, we showed that they suppress the efflux of fluorescent substrates and paclitaxel from the cells due to suppressing the ATPase activity of the transporters. The combined use of paclitaxel and ATP mimetics significantly increases its antitumor efficacy, including in cells with the multidrug resistance phenotype. The considered compounds are promising agents for the development of therapeutic efflux modulators, since they are not toxic at the given concentrations and do not induce the transporter overexpression. Moreover, the compounds overcome not only P-gp-mediated but also BCRP-mediated resistance of tumor cells.

Automated summary

The modulation of efflux transporters of the ABC family, especially P-glycoprotein, is crucial in overcoming transporter-mediated multidrug resistance in cancer therapy. A universal target for rational drug design is the nucleotide binding domain, which can be inhibited by ATP mimetics to suppress drug efflux. These compounds show promising potential as therapeutic efflux modulators, as they enhance the antitumor efficacy without inducing transporter overexpression.