2. Academic Validation
  3. Indole Derivatives as New Structural Class of Potent and Antiproliferative Inhibitors of Monocarboxylate Transporter 1 (MCT1; SLC16A1)

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

  • J Med Chem. 2023 Jan 12;66(1):657-676. doi: 10.1021/acs.jmedchem.2c01612.
Sachin Puri 1,  Katja Stefan 2,  Sharuk L Khan 3,  Jens Pahnke 2 4 5,  Sven Marcel Stefan 2 4,  Kapil Juvale 1
Affiliations

Affiliations

  • 1 Shobhaben Pratapbhai Patel School of Pharmacy & Technology Management, SVKM's NMIMS, V.L. Mehta Road, Vile Parle (W), Mumbai400056, India.
  • 2 Department of Pathology, Section of Neuropathology, Translational Neurodegeneration Research and Neuropathology Lab (www.pahnkelab.eu), University of Oslo and Oslo University Hospital, Sognsvannsveien 20, 0372Oslo, Norway.
  • 3 Department of Pharmaceutical Chemistry, N.B.S. Institute of Pharmacy, Ausa413520, Maharashtra, India.
  • 4 Drug Development and Chemical Biology Lab, Lübeck Institute of Experimental Dermatology (LIED), University of Lübeck and University Medical Center Schleswig-Holstein, Ratzeburger Allee 160, 23538Lübeck, Germany.
  • 5 Department of Pharmacology, Faculty of Medicine, University of Latvia, Jelgavas iela 4, 1004Ri̅ga, Latvia.
PMID: 36584238 DOI: 10.1021/acs.jmedchem.2c01612
Abstract

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).

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