Indole Derivatives as New Structural Class of Potent and Antiproliferative Inhibitors of Monocarboxylate Transporter 1 (MCT1; SLC16A1)

The solute carrier (SLC) monocarboxylate transporter
1 (MCT1; SLC16A1)
represents a promising target for the treatment of cancer; however,
the MCT1 modulator landscape is underexplored with only roughly 100
reported compounds. To expand the knowledge about MCT1 modulation,
we synthesized a library of 16 indole-based molecules and subjected
these to a comprehensive biological assessment platform. All compounds
showed functional inhibitory activities against MCT1 at low nanomolar
concentrations and great antiproliferative activities against the
MCT1-expressing cancer cell lines A-549 and MCF-7, while the compounds
were selective over MCT4 (SLC16A4). Lead compound 24 demonstrated
a greater potency than the reference compound, and molecular docking
revealed strong binding affinities to MCT1. Compound 24 led to cancer cell cycle arrest as well as apoptosis, and it showed
to sensitize these cancer cells toward an antineoplastic agent. Strikingly,
compound 24 had also significant inhibitory power against
the multidrug transporter ABCB1 and showed to reverse ABCB1-mediated
multidrug resistance (MDR).