Exploiting the co-reliance of tumours upon transport of amino acids and lactate: Gln and Tyr conjugates of MCT1 inhibitors

Reji N. Nair; Jitendra K. Mishra; Fangzheng Li; Mariola Tortosa; Chunying Yang; Joanne R. Doherty; Michael Cameron; John L. Cleveland; William R. Roush; Thomas D. Bannister

doi:10.1039/C5MD00579E

Exploiting the co-reliance of tumours upon transport of amino acids and lactate: Gln and Tyr conjugates of MCT1 inhibitors†‡

Reji N. Nair,§^a Jitendra K. Mishra,§^a Fangzheng Li,^a Mariola Tortosa,^a Chunying Yang,^b Joanne R. Doherty,^c Michael Cameron,^d John L. Cleveland,^b William R. Roush^a and Thomas D. Bannister*^a

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* Corresponding authors

^a Department of Chemistry, The Scripps Research Institute, 110 Scripps Way, Jupiter, FL 33458, USA
E-mail: tbannist@scripps.edu

^b Department of Tumor Biology, Moffitt Cancer Center & Research Institute, 12902 Magnolia Drive, Tampa, FL 33612, USA

^c Department of Cancer Biology, The Scripps Research Institute, 110 Scripps Way, Jupiter, FL 33458, USA

^d Department of Molecular Therapeutics, The Scripps Research Institute, 110 Scripps Way, Jupiter, FL 33458, USA

Abstract

Glutamine and tyrosine-based amino acid conjugates of monocarboxylate transporter types 1 and 2 inhibitors (MCT1/2) were designed, synthesized and evaluated for their potency in blocking the proliferation of a human B lymphoma cell line that expresses the transporters Asct2, LAT1 and MCT1. Appropriate placement of an amino acid transporter recognition element was shown to augment anti-tumour efficacy vs. Raji cells. Amino acid conjugation also improves the pharmacodynamic properties of experimental MCT1/2 inhibitors.

MedChemComm

Exploiting the co-reliance of tumours upon transport of amino acids and lactate: Gln and Tyr conjugates of MCT1 inhibitors†‡

Abstract

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Exploiting the co-reliance of tumours upon transport of amino acids and lactate: Gln and Tyr conjugates of MCT1 inhibitors

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