In This Issue pubs.acs.org/acsmedchemlett
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TARGETING VPS34 TO INHIBIT AUTOPHAGY Autophagy is the process by which cellular components are degraded and recycled. Given this role, autophagy is essential for maintaining cellular homeostasis, and mutations in autophagy-related genes have been implicated in a number of diseases including neurodegenerative disorders and cancer. The phosphatidylinositol 3-kinase, VPS34, has been implicated in playing a role in autophagy; thus, selective inhibitors of VPS34 are of interest as tools to interrogate the autophagy related processes and also hold potential for therapeutic development. Here, Honda et al. (DOI: 10.1021/acsmedchemlett.5b00335) describe the development of VPS34 inhibitors capable of inhibiting autophagy in cells. The authors identified a streamlined synthesis allowing for rapid analogue development and deliver compounds that are highly potent for inhibition of VPS34 and highly selective over a large number of lipid and protein kinases. The compounds were further optimized to deliver a potent, selective, and metabolically stable compound with suitable pharmacokinetic properties to enable a proof-of-concept in vivo study.
cysteine protease. Cocrystal structures of the oxyguanidine inhibitors bound to cruzain demonstrate these compounds are noncovalently bound to cruzain. This represents a rare example of noncovalent inhibition of a cysteine protease.
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USING BIOORTHOGONAL CHEMISTRY FOR PRETARGETED PET Bioorthogonal chemistry has demonstrated promise for biomedical imaging including pretargeted positron emission tomography (PET). In particular, electron-demand Diels− Alder cycloaddition (IEDDA) has been applied in pretargeted PET and SPECT imaging using 64Cu and 111In labeled tetrazines. Unfortunately, high lipophilicity has presented a challenge with many tetrazine derivatives leading to unfavorable pharmacokinetics and hampering their use in quantitative PET analysis, and new IEDDA ligands with improved pharmacokinetics are being sought. Due to its widespread availability and optimal physical properties, 18F appears as an ideal isotope for use in pretargeted PET. In this issue, Keinänen et al. (DOI: 10.1021/acsmedchemlett.5b00330) report the synthesis and biological evaluation of a new 18F-labeled tetrazine derivative for use in pretargeted PET imaging. The herein reported glycosylated tetrazine derivative exhibited low lipophilicity and demonstrated favorable in vivo pharmacokinetics with low accumulation in liver, preferable elimination to urine, and low level of in vivo defluorination. This work is the first reported evaluation of the influence of glycosylation on reaction kinetics and pharmacokinetics of tetrazines.
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FINDING NEW WAYS TO TARGET NEGLECTED TROPICAL DISEASES Chagas’ disease is a deadly vector-borne disease caused by the protozoan parasite Trypanosoma cruzi. Available therapeutics for this neglected tropical disease include benznidazole and nifurtimox, which are highly effective at killing the parasite and curing disease when administered shortly after infection has taken place. Unfortunately, if treatment is not administered early on during infection, the efficacy of these drugs is dramatically reduced and therapeutic intervention during later stages of disease aims to merely reduce disease progression. With the increased spread of Chagas’ disease around the world, ineffective treatment in latter stages of disease, toxicity concerns, and development of resistance, there is a growing impetus to find new therapeutic options. The major cysteine protease of T. cruzi, cruzain, has been identified as a novel potential target for therapeutic development. In this issue, Jones et al. (DOI: 10.1021/acsmedchemlett.5b00336) describe the synthesis and evaluation of a series of compounds with inhibitory activity against cruzain. The oxyguanidine analogues of the cysteine protease inhibitor WRR-483 designed here demonstrate comparable potency to previously prepared vinyl sulfone cruzain inhibitors. Despite the similar kinetic analysis to these earlier compounds, the authors demonstrate different binding interactions with the © 2016 American Chemical Society
Published: January 14, 2016 1
DOI: 10.1021/acsmedchemlett.5b00494 ACS Med. Chem. Lett. 2016, 7, 1−1
