In This Issue Cite This: ACS Med. Chem. Lett. 2019, 10, 682−683
ACS Med. Chem. Lett. 2019.10:682-683. Downloaded from pubs.acs.org by 5.62.157.133 on 05/18/19. For personal use only.
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HIGH-RESOLUTION CRYSTAL STRUCTURE OF ENDOPLASMIC RETICULUM AMINOPEPTIDASE 1 WITH BOUND PHOSPHINIC TRANSITION-STATE ANALOGUE INHIBITOR The zinc metalloprotease endoplasmic reticulum aminopeptidase 1 (ERAP1) is involved in the generation of antigenic peptides and is an attractive target for immunology and cancer immunotherapy. In their Featured Letter, Stratikos and colleagues disclose the first high-resolution crystal structure of ERAP1 (DOI: 10.1021/ acsmedchemlett.9b00002). The protein was found to be in its closed form and was cocrystallized with inhibitor DG046. The primary amine of DG046 forms multiple salt bridges with acidic residues, and the phosphinic acid moiety adopted transition state analog geometry, coordinating to the zinc center. While these ligand−protein interactions are conserved in cocrystal structures of aminophosphinic acids bound to homologous proteases ERAP2 and IRAP, the orientation of the aryl P1 residue is different, likely as a result of active site residue differences between the three proteins. Intriguingly, two components of the crystallization buffer were also found to occupy distal regions of the substrate pocket of ERAP1. The authors speculate that these sites may accommodate the binding of long peptide substrates or serve as allosteric binding sites that modulate protease activity. The high-resolution ERAP1 structure along with new insights about additional binding domains may facilitate the discovery of new and selective inhibitors.
synthesized a library of RNA splicer analogs based on the hypothesis that splicing may enhance PTCR and screened compounds using an immunofluorescence assay developed by some of the authors. The beneficial effect of compounds was measured as an enhancement ratio (ER) of PTCR of G418 with a potentiator versus G418 alone. Quantitative Western blot analysis was used to confirm hits and generate structure−activity relationships. Through this process, six 2-aminothiazole-4carboxamides emerged as the most potent enhancers. Although the mechanism of aminoglycoside induced PTCR enhancement is not known, the authors propose that enhancers may be interacting with a target upstream of ribose function. Their future work will focus on identifying such targets as well as to further optimize enhancer compounds to enable the use of aminoglycosides at subtoxic levels.
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DISCOVERY OF NOVEL PYRIDO-PYRIDAZINONE DERIVATIVES AS FER TYROSINE KINASE INHIBITORS WITH ANTITUMOR ACTIVITY FER is a kinase that is involved in cell migration. It has also been implicated in multiple invasive cancers, making it a relevant target for oncology; however, research in this area has been limited. In this issue, Taniguchi and colleagues report the discovery of novel pyrido-pyridazinone FER inhibitors (DOI: 10.1021/ acsmedchemlett.8b00631). Their initial hit, a moderately potent trisubstituted pyridine, was identified through an HTS of an internal chemical library. Subsequent optimization studies showed that C5-substitution on the pyridine ring could improve potency, with a cyano-substituent providing a 200-fold boost in potency. An X-ray cocrystal structure of the cyanopyridine bound to FES, a kinase with high homology to FER, revealed that the nitrile forms a hydrogen bond with the catalytic lysine. In addition, the primary amide substituent makes a two-point hinge interaction, and an adjacent phenyl amine forms an intramolecular hydrogen bond with the amide. These structural insights rationalized structure−activity relationship investigations that showed that both substituents were essential for potency. Further optimization yielded lead compound pyridopyridazinione DS21360717, a potent FER inhibitor with high permeability. This compound showed a good pharmacokinetic profile in mouse and moderate oral bioavailability. Importantly, DS21360717 showed dose-dependent growth inhibition in a FER-expressing tumor model. Based on these compelling
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2-AMINOTHIAZOLE-4-CARBOXAMIDES ENHANCE READTHROUGH OF PREMATURE TERMINATION CODONS BY AMINOGLYCOSIDES DNA mutations that result in premature termination codons (PTC) prevent the synthesis of full-length protein and are involved in a variety of human diseases. While aminoglycosides such as G418 are known to interact with ribosomes to induce PTC readthrough (PTCR), they are too toxic for use in humans at the required doses. In this issue, Grierson, Roberge, and co-workers describe the identification of compounds that potentiate PTCR activity of G418 (DOI: 10.1021/acsmedchemlett.8b00610). They © 2019 American Chemical Society
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Published: May 9, 2019 682
DOI: 10.1021/acsmedchemlett.9b00185 ACS Med. Chem. Lett. 2019, 10, 682−683
ACS Medicinal Chemistry Letters
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results, further characterization and optimization of this lead compound is underway.
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DOI: 10.1021/acsmedchemlett.9b00185 ACS Med. Chem. Lett. 2019, 10, 682−683
