Our team has developed homology models of monocarboxylate transporters (MCTs) 1 and 4 based on the published structure of the glycerol phosphate transporter GlpT. We chose GlpT due to its high amino acid sequence similarity to the MCTs in the transmembrane domains. The MCT1 structure has been used successfully in the design of potent inhibitors of MCT1 that possess low nM potency in cell-based assays, have acceptable <i>in vivo</i> stability and are currently being evaluated in animal xenograft models of various MCT1-dependent cancers.  These MCT1 inhibitors lack activity against the MCT4 isoform, however, and MCT4 also plays a key role in the progression of many tumor types. Observations from our models have shown sequence differences for MCT4 relative to the MCT1 isoform leading to different structural requirements for effective ligand binding. Utilizing the information from the models and the SAR of developed MCT1 inhibitors, we aim to identify inhibitors specific for MCT4 and to also design dual MCT1 / MCT4 inhibitors.

Homology model guided design and synthesis of MCT1 and four inhibitors

251st National Meeting (2016)

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