Tumor cells require a constant supply of essential and nonessential amino acids to support their growth. To achieve this they trap amino acids by expressing high levels of Asct2 and LAT1 transporters. Cleveland group has shown that tumor cells deal with lactate dilemma by markedly upregulating the expression of transporters that direct lactate efflux, specifically the monocarboxylate transporters Mct1 and/or Mct4. These are 12-membrane pass bidirectional exchange transporters and little has been known regarding control of their expression. Since very few compounds having high affinity for these transporters are known, every little effort has been done to study how disruptions in lactate transport may impede tumor cell viability.The Asct2 Gln transporter is highly expressed in Myc-driven lymphomas implying that agents that block Asct2 may be effective therapeutics, though none are known yet. An inhibitor for Asct2 may be exploited to be a tumor cell delivery device; i.e., a glutamine micic could be selectively concentrated near or within tumor cell. The glutamine like compound could then deliver the anti-Mct1-specific agent. Since tumor type that is chosen for therapy would over express Mct1 as well as Asct2, this double amplification scenario should result in high efficacy with an acceptable therapeutic index.AstraZeneca has reported few of its novel compounds which are active in inhibiting tumors. Based on the structural model, we have been using the art and skill of organic synthesis to synthesize new analogs with different alkyl and aryl groups, linkers and terminal attachment with glutamine. The compounds synthesized are purified, analyzed and then submitted to cancer biology, where their activities are tested. We have synthesized more than 35 compounds with a variety of heterocycles and found that these compounds are active in transporting amino acids as well as inhibiting tumors. The synthesis and SAR of all the compounds studied will be discussed in this presentation.

Targeting tumors by their addiction to amino acids: Glutamine�containing anticancer agents

247th National Meeting (2014)

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