Current immunosuppressive therapies act on T lymphocytes by modulation of cytokine production, modulation of signaling pathways or by inhibition of the enzymes of nucleotide biosynthesis. We have identified a previously unknown series of immunomodulatory compounds that potently inhibit human and rat T lymphocyte proliferation in vitro and in vivo in immune-mediated animal models of disease, acting by a novel mechanism. Here we identify the target of these compounds, the monocarboxylate transporter MCT1 (SLC16A1), using a strategy of photoaffinity labeling and proteomic characterization. We show that inhibition of MCT1 during T lymphocyte activation results in selective and profound inhibition of the extremely rapid phase of T cell division essential for an effective immune response. MCT1 activity, however, is not required for many stages of lymphocyte activation, such as cytokine production, or for most normal physiological functions. By pursuing a chemistry-led target identification strategy, we have discovered that MCT1 is a previously unknown target for immunosuppressive therapy and have uncovered an unsuspected role for MCT1 in immune biology.

A visible-light-mediated late-stage aminocarbonylation of unactivated alkyl iodides with stoichiometric amounts of carbon monoxide is presented. The method provides a mild, one-step route to [carbonyl-13/14 C] alkyl amides, thereby reducing radioactive waste, and handling of radioactive materials. Easily accessible and low-cost equipment and a palladium catalyst were successfully used for the synthesis of a wide range of alkyl amides.

Metal-catalysed exchange has been used extensively in the laboratories of AstraZeneca plc at R&D Charnwood to label a variety of molecules of pharmaceutical interest with the isotopes of deuterium and tritium. Despite early prejudices against the use of tritiated compounds, particularly in ADME studies, the development of directed isotopic exchange techniques has enabled timely and economic support for many pharmaceutical projects.