In This Issue pubs.acs.org/acsmedchemlett
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REDUCING NEGATIVITY TO INCREASE EFFICACY Antifolates have been developed for treatment of a variety of diseases, including both infectious diseases and various malignancies. The increasing emergence of antibiotic-resistance emphasizes the need for new antibiotics, and development of new antifolates could help to fulfill this need. Although classical antifolates, such as methotrexate, which are used in the treatment of cancer, are readily transported into human cells, and are potent inhibitors of the essential enzyme dihydrofolate reductase (DHFR), these negatively charged compounds are poor antibacterial agents owing to a lack of cell permeability. In this issue Scocchera et al. (DOI: 10.1021/acsmedchemlett.6b00120) address the critical problem of poor bacterial cell membrane permeability of classical antifolates by developing zwitterionic compounds. The authors first developed a series of novel, propargyl-linked inhibitors of DHFR that passively diffuse through membranes and potently inhibit bacterial cell growth. Combining the features of the propargyl-linked antifolates with the opportunity to mimic the additional contacts that the classical antifolates have with the enzyme, they designed and synthesized hybrid zwitterionic compounds. These zwitterionic propargyllinked antifolates are highly potent against both the enzyme and Gram-positive bacteria and show promising potency against Gram-negative bacteria. This work serves to advance the field of DHFR antibacterial development and present a series of new lead compounds for further development.
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IMPROVING DISCOVERY OF PET TRACERS Positron emission tomography (PET) imaging is a valuable tool for assessment of CNS target engagement in clinical trials. Development of a novel PET imaging tracer, however, requires investment of already limited resources in today’s research environment. A successful endeavor, therefore, requires thoughtful design of assays and flow scheme filters in order to efficiently identify the most promising candidates prior to advancement into costly in vivo PET imaging studies. The work by Hu et al. (DOI: 10.1021/acsmedchemlett.6b00185) reports the development of a PDE10A PET imaging tracer using a select combination of in vitro filters, in vitro binding off-rate measurements, and a LC-MS/MS platform. The strategy used here facilitated query from multiple scaffolds and allowed for the rapid scan of the large number of analogs within each structural series. Three tracer candidates were selected for an in vivo PET imaging study, and one fulfilled the target profile to become the PDE10A PET tracer clinical candidate, AMG 580.
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A VACCINE COMPONENT ACTS AS AN ERAP INHIBITOR Endoplasmic reticulum aminopeptidase 1 (ERAP1) generates antigenic peptides for presentation by Major Histocompatibility Class I molecules and indirectly regulates cytotoxic immune responses toward aberrant or diseased cells. Recently, ERAP1 has emerged as an attractive target for the development of novel immunotherapeutic approaches for the treatment of both cancer and autoimmune diseases. Here, Stamogiannos et al. (DOI: 10.1021/acsmedchemlett.6b00084) combined structure based virtual screening with biochemical characterization and discovered novel scaffolds as promising ERAP1 inhibitors. Interestingly, thimerosal, a common vaccine component, was found to be a selective ERAP1 inhibitor against other ER and cytosolic aminopeptidases. Although ERAP inhibitors have been previously described, the inhibitors discovered here exhibit improved potency and selectivity, thus overcoming some of the limitations of earlier compounds. © 2016 American Chemical Society
Published: July 14, 2016 655
DOI: 10.1021/acsmedchemlett.6b00260 ACS Med. Chem. Lett. 2016, 7, 655−655
