- Nonpeptidic, Polo-Box Domain-Targeted Inhibitors of PLK1 Block Kinase Activity, Induce Its Degradation and Target-Resistant Cells
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PLK1, polo-like kinase 1, is a central player regulating mitosis. Inhibition of the subcellular localization and kinase activity of PLK1 through the PBD, polo-box domain, is a viable alternative to ATP-competitive inhibitors, for which the development of resistance and inhibition of related PLK family members are concerns. We describe novel nonpeptidic PBD-binding inhibitors, termed abbapolins, identified through successful application of the REPLACE strategy and demonstrate their potent antiproliferative activity in prostate tumors and other cell lines. Furthermore, abbapolins show PLK1-specific binding and inhibitory activity, as measured by a cellular thermal shift assay and an ability to block phosphorylation of TCTP, a validated target of PLK1-mediated kinase activity. Additional evidence for engagement of PLK1 was obtained through the unique observation that abbapolins induce PLK1 degradation in a manner that closely matches antiproliferative activity. Moreover, abbapolins demonstrate antiproliferative activity in cells that are dramatically resistant to ATP-competitive PLK1 inhibitors.
- Chapagai, Danda,Ramamoorthy, Gurusankar,Varghese, Jessy,Nurmemmedov, Elmar,McInnes, Campbell,Wyatt, Michael D.
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supporting information
p. 9916 - 9925
(2021/07/26)
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- Potentiation of the fosmidomycin analogue FR 900098 with substituted 2-oxazolines against Francisella novicida
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A library of 33 compounds was screened for potentiation of the antibiotic FR 900098 against the Francisella tularensis surrogate Francisella novicida. From the screen a highly potent 2-oxazoline adjuvant was discovered capable of potentiating FR 900098 with a 1000-fold reduction in MIC against the Francisella sub-species F. novicida and F. philomiragia.
- Stephens, Matthew D.,Yodsanit, Nisakorn,Melander, Christian
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p. 1952 - 1956
(2016/10/22)
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- Discovery and characterization of potent thiazoles versus methicillin- and vancomycin-resistant Staphylococcus aureus
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Methicillin- and vancomycin-resistant Staphylococcus aureus (MRSA and VRSA) infections are growing global health concerns. Structure-activity relationships of phenylthiazoles as a new antimicrobial class have been addressed. We present 10 thiazole derivatives that exhibit strong activity against 18 clinical strains of MRSA and VRSA with acceptable PK profile. Three derivatives revealed an advantage over vancomycin by rapidly eliminating MRSA growth within 6 h, and no derivatives are toxic to HeLa cells at 11 μg/mL.
- Mohammad, Haroon,Mayhoub, Abdelrahman S.,Ghafoor, Adil,Soofi, Muhammad,Alajlouni, Ruba A.,Cushman, Mark,Seleem, Mohamed N.
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p. 1609 - 1615
(2014/03/21)
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- Discotic Liquid Crystals: Relation between Molecular Structure and Discogenic Properties of Disk-shaped Compounds, Non-liquid Crystalline Esters of myo-Inositol and Mytilitol
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A modified synthesis of mytilitol and the synthesis of various esters of the cyclitols myo-inositol (1a) and mytilitol (2a) is described.Because of steric reasons all these derivatives of the two naturally occuring compounds exhibit no discotic mesophases
- Kohne, Bernd,Praefcke, Klaus,Stephan, Werner,Nuernberg, Peter
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p. 981 - 986
(2007/10/02)
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- Synthesis of Unbranched 4-Alkylbenzaldehydes
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The preparation of unbranched 4-alkylbenzaldehydes free of positional and branched-chain isomers by different methods is described.A one-step preparation of the aldehydes is reported which involves the direct hydrogenation of a Friedel-Craft's complex in the presence of Pd/C catalyst.
- Osman, Maged A.
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p. 2448 - 2449
(2007/10/02)
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- First Liquid Crystal Azulene Derivatives
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Various azulene derivatives as a new type of coloured liquid crystals have been synthesized.Their mesomorphic behaviour is described. - Keywords: Azulenes, Coloured Liquid Crystals, Nematic Phases
- Praefcke, Klaus,Schmidt, Dietmar
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p. 375 - 378
(2007/10/02)
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- SYNTHESIS AND MESOMORPHIC PROPERTIES OF THE HOMOLOGOUS SERIES OF 4-ALKYL OR ALKOXY-4 prime -BROMO OR CYANOTOLANES.
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A homologous series of 4-alkyl or alkoxy-4 prime -bromo or cyanotolanes in which the alkyl group is C//4 yields C//1//0 and the alkoxy group is C//1 yields C//1//2, was prepared. Interphase transitions between solid, mesomorphic and isotropic phases were studied by hot stage microscopy and differential scanning calorimeter. The bromo compounds have a smectic polymorphism. Three pure products of cyano derivatives with the chains C//9H//1//9O, C//1//0H//2//1O amd C//1//0H//2//1 present an enantiotropic or monotropic reentrant nematic phase at atmospheric pressure. The reentrant phenomenon itself is discussed as well as the absence of correlation between T//N//A/T//N//I McMillan parameter and the heat of transition. A plot of the nematic isotropic transition temperatures against the number of carbon atoms in the alkoxy chain shows the usual odd even effect.
- Tinh,Pourrere,Destrade
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p. 125 - 139
(2007/10/02)
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