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1.
Roecker AJ Coleman PJ Mercer SP Schreier JD Buser CA Walsh ES Hamilton K Lobell RB Tao W Diehl RE South VJ Davide JP Kohl NE Yan Y Kuo LC Li C Fernandez-Metzler C Mahan EA Prueksaritanont T Hartman GD 《Bioorganic & medicinal chemistry letters》2007,17(20):5677-5682
Inspired by previous efforts in the pyrazolobenzoxazine class of KSP inhibitors, the design and synthesis of 1,4-diaryl-4,5-dihydropyrazole inhibitors of KSP are described. Crystallographic evidence of binding mode and in vivo potency data is also highlighted. 相似文献
2.
A three-dimensional pharmacophore model was developed based on 25 currently available KSP (kinesin spindle protein) inhibitors in Catalyst software package. The best pharmacophore hypothesis (Hypo1), consisting of four chemical features (one hydrogen-bond acceptor, one hydrogen-bond donor, one aromatic ring, and one hydrophobic group), has a correlation coefficient of 0.965. The results of our study provide a valuable tool in designing new leads with desired biological activity by virtual screening. 相似文献
3.
Pinkerton AB Lee TT Hoffman TZ Wang Y Kahraman M Cook TG Severance D Gahman TC Noble SA Shiau AK Davis RL 《Bioorganic & medicinal chemistry letters》2007,17(13):3562-3569
We have identified and synthesized a series of thiophene containing inhibitors of kinesin spindle protein. SAR studies led to the synthesis of 33, which was co-crystallized with KSP and determined to bind to an allosteric pocket previously described for other known KSP inhibitors. 相似文献
4.
Coleman PJ Schreier JD Cox CD Fraley ME Garbaccio RM Buser CA Walsh ES Hamilton K Lobell RB Rickert K Tao W Diehl RE South VJ Davide JP Kohl NE Yan Y Kuo L Prueksaritanont T Li C Mahan EA Fernandez-Metzler C Salata JJ Hartman GD 《Bioorganic & medicinal chemistry letters》2007,17(19):5390-5395
3,5-diaryl-4,5-dihydropyrazoles were discovered to be potent KSP inhibitors with excellent in vivo potency. These enzyme inhibitors possess desirable physical properties that can be readily modified by incorporation of a weakly basic amine. Careful adjustment of amine basicity was essential for preserving cellular potency in a multidrug resistant cell line while maintaining good aqueous solubility. 相似文献
5.
Fraley ME Garbaccio RM Arrington KL Hoffman WF Tasber ES Coleman PJ Buser CA Walsh ES Hamilton K Fernandes C Schaber MD Lobell RB Tao W South VJ Yan Y Kuo LC Prueksaritanont T Shu C Torrent M Heimbrook DC Kohl NE Huber HE Hartman GD 《Bioorganic & medicinal chemistry letters》2006,16(7):1775-1779
The evolution of 2,4-diaryl-2,5-dihydropyrroles as inhibitors of KSP is described. Introduction of basic amide and urea moieties to the dihydropyrrole nucleus enhanced potency and aqueous solubility, simultaneously, and provided compounds that caused mitotic arrest of A2780 human ovarian carcinoma cells with EC(50)s<10nM. Ancillary hERG activity was evaluated for this series of inhibitors. 相似文献
6.
Luo L Parrish CA Nevins N McNulty DE Chaudhari AM Carson JD Sudakin V Shaw AN Lehr R Zhao H Sweitzer S Lad L Wood KW Sakowicz R Annan RS Huang PS Jackson JR Dhanak D Copeland RA Auger KR 《Nature chemical biology》2007,3(11):722-726
The mitotic kinesin KSP (kinesin spindle protein, or Eg5) has an essential role in centrosome separation and formation of the bipolar mitotic spindle. Its exclusive involvement in the mitotic spindle of proliferating cells presents an opportunity for developing new anticancer agents with reduced side effects relative to antimitotics that target tubulin. Ispinesib is an allosteric small-molecule KSP inhibitor in phase 2 clinical trials. Mutations that attenuate ispinesib binding to KSP have been identified, which highlights the need for inhibitors that target different binding sites. We describe a new class of selective KSP inhibitors that are active against ispinesib-resistant forms of KSP. These ATP-competitive KSP inhibitors do not bind in the nucleotide binding pocket. Cumulative data from generation of resistant cells, site-directed mutagenesis and photo-affinity labeling suggest that they compete with ATP binding via a novel allosteric mechanism. 相似文献
7.
Rickert KW Schaber M Torrent M Neilson LA Tasber ES Garbaccio R Coleman PJ Harvey D Zhang Y Yang Y Marshall G Lee L Walsh ES Hamilton K Buser CA 《Archives of biochemistry and biophysics》2008,469(2):220-231
The kinesin spindle protein (KSP, also known as Eg5) is essential for the proper separation of spindle poles during mitosis, and inhibition results in mitotic arrest and the formation of characteristic monoaster spindles. Several distinct classes of KSP inhibitors have been described previously in the public and patent literature. However, most appear to share a common induced-fit allosteric binding site, suggesting a common mechanism of inhibition. In a high-throughput screen for inhibitors of KSP, a novel class of thiazole-containing inhibitors was identified. Unlike the previously described allosteric KSP inhibitors, the thiazoles described here show ATP competitive kinetic behavior, consistent with binding within the nucleotide binding pocket. Although they bind to a pocket that is highly conserved across kinesins, these molecules exhibit significant selectivity for KSP over other kinesins and other ATP-utilizing enzymes. Several of these compounds are active in cells and produce a phenotype similar to that observed with previously published allosteric inhibitors of KSP. 相似文献
8.
Cox CD Breslin MJ Mariano BJ Coleman PJ Buser CA Walsh ES Hamilton K Huber HE Kohl NE Torrent M Yan Y Kuo LC Hartman GD 《Bioorganic & medicinal chemistry letters》2005,15(8):2041-2045
Optimization of high-throughput screening (HTS) hits resulted in the discovery of 3,5-diaryl-4,5-dihydropyrazoles as potent and selective inhibitors of KSP. Dihydropyrazole 15 is a potent, cell-active KSP inhibitor that induces apoptosis and generates aberrant mitotic spindles in human ovarian carcinoma cells at low nanomolar concentrations. X-ray crystallographic evidence is presented which demonstrates that these inhibitors bind in an allosteric pocket of KSP distant from the nucleotide and microtubule binding sites. 相似文献
9.
Cox CD Torrent M Breslin MJ Mariano BJ Whitman DB Coleman PJ Buser CA Walsh ES Hamilton K Schaber MD Lobell RB Tao W South VJ Kohl NE Yan Y Kuo LC Prueksaritanont T Slaughter DE Li C Mahan E Lu B Hartman GD 《Bioorganic & medicinal chemistry letters》2006,16(12):3175-3179
Molecular modeling in combination with X-ray crystallographic information was employed to identify a region of the kinesin spindle protein (KSP) binding site not fully utilized by our first generation inhibitors. We discovered that by appending a propylamine substituent at the C5 carbon of a dihydropyrazole core, we could effectively fill this unoccupied region of space and engage in a hydrogen-bonding interaction with the enzyme backbone. This change led to a second generation compound with increased potency, a 400-fold enhancement in aqueous solubility at pH 4, and improved dog pharmacokinetics relative to the first generation compound. 相似文献
10.
Cox CD Breslin MJ Whitman DB Coleman PJ Garbaccio RM Fraley ME Zrada MM Buser CA Walsh ES Hamilton K Lobell RB Tao W Abrams MT South VJ Huber HE Kohl NE Hartman GD 《Bioorganic & medicinal chemistry letters》2007,17(10):2697-2702
Installation of a C2-aminopropyl side chain to the 2,4-diaryl-2,5-dihydropyrrole series of kinesin spindle protein (KSP) inhibitors results in potent, water soluble compounds, but the aminopropyl group induces susceptibility to cellular efflux by P-glycoprotein (Pgp). We show that by carefully modulating the basicity of the amino group by beta-fluorination, this series of inhibitors maintains potency against KSP and has greatly improved efficacy in a Pgp-overexpressing cell line. The discovery that cellular efflux by Pgp can be overcome by carefully modulating the basicity of an amine may be of general use to medicinal chemists attempting to transform leading compounds into cancer cell- or CNS-penetrant drugs. 相似文献
11.
mTOR (mammalian target of rapamycin) forms two distinct types of complex, mTORC (mTOR complex) 1 and 2. Rapamycin inhibits some of the functions of mTORC1, whereas newly developed mTOR kinase inhibitors interfere with the actions of both types of complex. We have explored the effects of rapamycin and mTOR kinase inhibitors on general protein synthesis and, using a new stable isotope-labelling method, the synthesis of specific proteins. In HeLa cells, rapamycin only had a modest effect on total protein synthesis, whereas mTOR kinase inhibitors decreased protein synthesis by approx. 30%. This does not seem to be due to the ability of mTOR kinase inhibitors to block the binding of eIFs (eukaryotic initiation factors) eIF4G and eIF4E. Analysis of the effects of the inhibitors on the synthesis of specific proteins showed a spectrum of behaviours. As expected, synthesis of proteins encoded by mRNAs that contain a 5'-TOP (5'-terminal oligopyrimidine tract) was impaired by rapamycin, but more strongly by mTOR kinase inhibition. Several proteins not known to be encoded by 5'-TOP mRNAs also showed similar behaviour. Synthesis of proteins encoded by 'non-TOP' mRNAs was less inhibited by mTOR kinase inhibitors and especially by rapamycin. The implications of our findings are discussed. 相似文献
12.
Specificity of protein synthesis inhibitors in the inhibition of encephalomyocarditis virus replication. 总被引:1,自引:1,他引:0
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Effect of protein synthesis inhibitors on encephalomyocarditis virus production in L-cells was studied. Inhibition of initiation by hypertonicity, harringtonine, or pactamycin decreased viral protein synthesis to a lesser extent than that of host. Virus yield was unaffected or actually enhanced by low concentrations of these inhibitors. On the contrary, the elongation inhibitors cycloheximide, anisomycin, and emetine, shown previously to inhibit viral protein synthesis preferentially, had a greater effect on virus yield than on overall protein synthesis. These results support our earlier proposal that the antiviral activity of cycloheximide derives from its specific effect on the rate of elongation of protein synthesis, and that elongation inhibitors in general may show varying degrees of specific antiviral activity. 相似文献
13.
Kinesin spindle protein (KSP) inhibitors are a promising class of anticancer agents that cause mitotic arrest in cells from a failure to form functional bipolar mitotic spindles. Here, we report the design, synthesis and biological evaluation of a novel series of 1,4-dihydroquinolin-4-ones and 1,2,3,4-tetrahydroquinazolin-4-ones using de novo design method. The synthesized compound was evaluated and proved to have potent inhibitory activities in the KSP ATPase. Compounds 15j and 15p show potent inhibitory activities in cell proliferation assays. Preferred compound 15j markedly induced G2/M phase cell cycle arrest with characteristic monoastral spindles and subsequent cell death in A549 cells. In vivo evaluation of 15j on the growth of transplantable S180 sarcoma in mice suggested its therapeutic potential for further development. 相似文献
14.
Chandrasekaran Balakumar Muthusamy Ramesh Chuin Lean Tham Samukelisiwe Pretty Khathi Frank Kozielski Cherukupalli Srinivasulu 《Journal of biomolecular structure & dynamics》2013,31(14):3687-3704
Kinesin spindle protein (KSP) belongs to the kinesin superfamily of microtubule-based motor proteins. KSP is responsible for the establishment of the bipolar mitotic spindle which mediates cell division. Inhibition of KSP expedites the blockade of the normal cell cycle during mitosis through the generation of monoastral MT arrays that finally cause apoptotic cell death. As KSP is highly expressed in proliferating/cancer cells, it has gained considerable attention as a potential drug target for cancer chemotherapy. Therefore, this study envisaged to design novel KSP inhibitors by employing computational techniques/tools such as pharmacophore modelling, virtual database screening, molecular docking and molecular dynamics. Initially, the pharmacophore models were generated from the data-set of highly potent KSP inhibitors and the pharmacophore models were validated against in house test set ligands. The validated pharmacophore model was then taken for database screening (Maybridge and ChemBridge) to yield hits, which were further filtered for their drug-likeliness. The potential hits retrieved from virtual database screening were docked using CDOCKER to identify the ligand binding landscape. The top-ranked hits obtained from molecular docking were progressed to molecular dynamics (AMBER) simulations to deduce the ligand binding affinity. This study identified MB-41570 and CB-10358 as potential hits and evaluated these experimentally using in vitro KSP ATPase inhibition assays. 相似文献
15.
The object of this work was to study how the synthesis of protein, RNA and DNA in Escherichia coli M17 and its viability were influenced by chloramphenicol (50 and 300 micrograms/ml) an inhibitor of protein biosynthesis, and sodium azide (200 and 2000 microM) and aminazine (50 micrograms/ml), inhibitors of respiration. The exposed were inhibitors with the bacteria for 60 min at room temperature and for 1-4 months at -10 degrees C. The inhibition of the E. coli viability by chloramphenicol was shown to be reversible. The respiration inhibitors stabilized its viability upon storage at -10 degrees C for one month. The inhibitors were found to produce a different effect on the synthesis of RNA and protein in E. coli. The rates of DNA synthesis hardly changed. No correlation was established between changes in the synthesis of protein and nucleic acids by E. coli after the action of the inhibitors and its viability. 相似文献
16.
G M Iakovleva 《Bioorganicheskaia khimiia》1987,13(4):437-497
The review deals with directed synthesis of specific enzyme inhibitors. They are classified within the framework of the mechanistic approach, namely, stable analogues of substrates, which form enzyme complexes mimicking the Michaelis complex or those which influence the chemical stages of enzyme catalysis; conformational inhibitors; substrate analogues participating in enzyme reactions and producing modified products; suicide inhibitors; stage inhibitors (inhibitors influencing certain stages of enzyme reaction); transition state analogues; multisubstrate analogues and collected substrates. Types of chemical modification used in synthesis of the specific inhibitors are discussed. Some possibilities of the quantity structure-activity relationship methods, computer modelling and molecular graphics in designing the optimal structure of inhibitors are mentioned. 相似文献
17.
Chen Z Kim SH Barbosa SA Huynh T Tortolani DR Leavitt KJ Wei DD Manne V Ricca CS Gullo-Brown J Poss MA Vaccaro W Salvati ME 《Bioorganic & medicinal chemistry letters》2006,16(3):628-632
The synthesis and SAR of a series of pyrrolopyridazine MEK inhibitors are reported. Optimal activity was achieved by incorporation of a 4-phenoxyaniline substituent at C4 and an acylated amine at C6. 相似文献
18.
19.
Frank Boschelli Jennifer M. Golas Roseann Petersen Vincent Lau Lei Chen Diane Tkach Qiang Zhao Dave S. Fruhling Hao Liu Chaneun Nam Kim T. Arndt 《Cell stress & chaperones》2010,15(6):913-927
Cancer cells are exposed to external and internal stresses by virtue of their unrestrained growth, hostile microenvironment, and increased mutation rate. These stresses impose a burden on protein folding and degradation pathways and suggest a route for therapeutic intervention in cancer. Proteasome and Hsp90 inhibitors are in clinical trials and a 20S proteasome inhibitor, Velcade, is an approved drug. Other points of intervention in the folding and degradation pathway may therefore be of interest. We describe a simple screen for inhibitors of protein synthesis, folding, and proteasomal degradation pathways in this paper. The molecular chaperone-dependent client v-Src was fused to firefly luciferase and expressed in HCT-116 colorectal tumor cells. Both luciferase and protein tyrosine kinase activity were preserved in cells expressing this fusion construct. Exposing these cells to the Hsp90 inhibitor geldanamycin caused a rapid reduction of luciferase and kinase activities and depletion of detergent-soluble v-Src::luciferase fusion protein. Hsp70 knockdown reduced v-Src::luciferase activity and, when combined with geldanamycin, caused a buildup of v-Src::luciferase and ubiquitinated proteins in a detergent-insoluble fraction. Proteasome inhibitors also decreased luciferase activity and caused a buildup of phosphotyrosine-containing proteins in a detergent-insoluble fraction. Protein synthesis inhibitors also reduced luciferase activity, but had less of an effect on phosphotyrosine levels. In contrast, certain histone deacetylase inhibitors increased luciferase and phosphotyrosine activity. A mass screen led to the identification of Hsp90 inhibitors, ubiquitin pathway inhibitors, inhibitors of Hsp70/Hsp40-mediated refolding, and protein synthesis inhibitors. The largest group of compounds identified in the screen increased luciferase activity, and some of these increase v-Src levels and activity. When used in conjunction with appropriate secondary assays, this screen is a powerful cell-based tool for studying compounds that affect protein synthesis, folding, and degradation. 相似文献
20.
Naud J Lemke C Goudreau N Beaulieu E White PD Llinàs-Brunet M Forgione P 《Bioorganic & medicinal chemistry letters》2008,18(11):3400-3404
The design and synthesis of tripeptide-based inhibitors of the HCV NS3 protease containing a novel P2-triazole is described. Replacement of the P2 quinoline with a triazole moiety provided a versatile handle which could be expediently modified to generate a diverse series of inhibitors. Further refinement by the incorporation of an aryl-substituted triazole and replacement of the P1 acid with an acyl sulfonamide ultimately provided inhibitors with interesting cellular activity. 相似文献