- Nonpeptidic, Polo-Box Domain-Targeted Inhibitors of PLK1 Block Kinase Activity, Induce Its Degradation and Target-Resistant Cells
-
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.
-
supporting information
p. 9916 - 9925
(2021/07/26)
-
- Discovery, biological evaluation, and structure-activity relationship of amidine based sphingosine kinase inhibitors
-
Sphingosine 1-phosphate (S1P), a potent phospholipid growth and trophic factor, is synthesized in vivo by two sphingosine kinases. Thus these kinases have been proposed as important drug targets for treatment of hyperproliferative diseases and inflammation. We report here a new class of amidine-based sphingosine analogues that are competitive inhibitors of sphingosine kinases exhibiting varying degrees of enzyme selectivity. These inhibitors display KI values in the submicromolar range for both sphingosine kinases and, in cultured vascular smooth muscle cells, decrease S1P levels and initiate growth arrest.
- Mathews, Thomas P.,Kennedy, Andrew J.,Kharel, Yugesh,Kennedy, Perry C.,Nicoara, Oana,Sunkara, Manjula,Morris, Andrew J.,Wamhoff, Brian R.,Lynch, Kevin R.,MacDonald, Timothy L.
-
experimental part
p. 2766 - 2778
(2010/09/04)
-
- Preparation of new substituted bis(benzoyl) peroxides under aqueous conditions in the presence of stearyltrimethylammonium chloride
-
A series of new substituted bis(benzoyl) peroxides has been synthesised from their corresponding acid chlorides in high yield. The reactions were carried out in aqueous sodium peroxide solution and butanone in the presence of 0.5% stearyltrimethylammonium chloride (STAC) at a temperature below 15°C. STAC improved the purity, and the fast addition improved the yield of the peroxides. Mass spectral analysis of substituted bis(benzoyl) peroxides using EI has been carried out for accurate mass determinations. Springer-Verlag 2003.
- Moorhoff, Cornelis M.,Braybrook, Carl
-
p. 397 - 405
(2007/10/03)
-
- Rigid amphiphiles for membrane protein manipulation
-
The two nonhomologous membrane proteins bacteriorhodopsin and bovine rhodopsin can be extracted from their native membranes by the rigid tripod amphiphile 1. Both proteins are maintained in a stable, soluble form, which is a prerequisite for crystallization. This new class of amphiphiles can be easily modified and could prove to be very useful for membrane protein manipulation.
- McQuade, D. Tyler,Quinn, Mariah A.,Yu, Seungju M.,Polans, Arthur S.,Krebs, Mark P.,Gellman, Samuel H.
-
p. 758 - 761
(2007/10/03)
-
- Mesomorphic Properties of Some 4,4'-Alkyl and Alkoxy Disubstituted Phenylbenzoates
-
A variety of new 4,4'-disubstituted phenylbenzoates with one and/or both substituents as alkyl (R) or alkoxy (RO) were prepared and their mesomorphic (liquid crystalline) properties determined for later use as standards for comparison with mesomorphic properties in other new 4,4'-disubstituted phenylbenzoates.Other esters of this type which had been previously reported, were prepared for physical studies of their mesophases and found to have different mesomorphic properties than those reported earlier.Still others were prepared to identify phases which were not determined previously.This paper presents new mesomorphic properties along with a comparison of the NMR spectra for the four possible analogs of these esters (R-R, R-OR), RO-R, RO-OR).Keywords: phenylbenzoates, mesogens, liquid crystals, NMR
- Neubert, Mary E.,Jirousek, Michael R.,Hanlon, Carol A.
-
p. 223 - 234
(2007/10/02)
-
- Synthesis of Unbranched 4-Alkylbenzaldehydes
-
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.
-
p. 2448 - 2449
(2007/10/02)
-
- SYNTHESIS AND MESOMORPHIC PROPERTIES OF THE HOMOLOGOUS SERIES OF 4-ALKYL OR ALKOXY-4 prime -BROMO OR CYANOTOLANES.
-
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
-
p. 125 - 139
(2007/10/02)
-