Structure-guided screening identifies Tucatinib as dual inhibitor for MCT1/2

Area of Science:

• Biochemistry
• Molecular Biology
• Cancer Research

Background:

• Cell surface glycoproteins like embigin form heterodimers with monocarboxylate transporters (MCTs), influencing their membrane trafficking and function.
• Cancer cells exhibit metabolic reprogramming, relying on MCTs for lactate transport to sustain glycolysis and maintain intracellular pH.
• Understanding MCT regulation is key to developing novel cancer inhibitors.

Purpose of the Study:

• Determine the cryo-electron microscopy (cryo-EM) structures of the human MCT2-embigin complex.
• Identify potential inhibitors of MCT1 and MCT2 transporters.
• Evaluate the efficacy and safety of identified inhibitors in preclinical cancer models.

Main Methods:

• Cryo-EM structure determination of the human MCT2-embigin complex in apo and AR-C155858-bound states.
• Virtual screening based on MCT1/2 structures to identify inhibitors.
• In vitro assays to assess inhibition of tumor cell proliferation and migration.
• In vivo studies using a mouse xenograft model to evaluate tumor growth inhibition.

Main Results:

• The cryo-EM structures reveal extensive interactions between embigin and MCT2, crucial for membrane localization and transport.
• Virtual screening identified Tucatinib as an effective inhibitor of pyruvate transport by both MCT1 and MCT2.
• Tucatinib demonstrated potent inhibition of cervical tumor cell proliferation and migration in vitro.
• Tucatinib significantly inhibited tumor growth in a mouse xenograft model with excellent biological safety.

Conclusions:

• The study provides molecular insights into the structural and functional mechanisms of MCT2.
• Tucatinib is identified as a novel dual inhibitor of MCT1 and MCT2 transporters.
• Tucatinib shows promise as a potential therapeutic agent for cancers dependent on MCT-mediated metabolism.