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排序方式: 共有289条查询结果,搜索用时 640 毫秒
61.
62.
Chen C Stearns B Hu T Anker N Santini A Arruda JM Campbell BT Datta P Aiyar J Munoz B 《Bioorganic & medicinal chemistry letters》2006,16(3):746-749
The SAR of the lead compound 3, a novel ligand for the alpha(2)delta subunit of voltage-gated calcium channels, was rapidly explored. Utilizing a parallel solution-phase Sn2Ar coupling approach, a focused library was obtained. The library was evaluated in vitro and afforded a series of analogues with improved potencies. The SAR trends of the library are also described. 相似文献
63.
The nucleation of microtubules requires protein complexes containing γ-tubulin, which are present in the cytoplasm and associate with the centrosome and with the mitotic spindle. We have previously shown that these interactions require the γ-tubulin targeting factor GCP-WD/NEDD1, which has an essential role in spindle formation. The recruitment of additional γ-tubulin to the centrosomes occurs during centrosome maturation at the G2/M transition and is regulated by the mitotic kinase Plk1. However, the molecular details of this important pathway are unknown and a Plk1 substrate that controls γ-tubulin recruitment has not been identified. Here we show that Plk1 associates with GCP-WD in mitosis and Plk1 activity contributes to phosphorylation of GCP-WD. Plk1 depletion or inhibition prevents accumulation of GCP-WD at mitotic centrosomes, but GCP-WD mutants that are defective in Plk1-binding and -phosphorylation still accumulate at mitotic centrosomes and recruit γ-tubulin. Moreover, Plk1 also controls the recruitment of other PCM proteins implicated in centrosomal γ-tubulin attachment (Cep192/hSPD2, pericentrin, Cep215/Cdk5Rap2). Our results support a model in which Plk1-dependent recruitment of γ-tubulin to mitotic centrosomes is regulated upstream of GCP-WD, involves multiple PCM proteins and therefore potentially multiple Plk1 substrates. 相似文献
64.
He S Ye Z Dobbelaar PH Bakshi RK Hong Q Dellureficio JP Sebhat IK Guo L Liu J Jian T Lai Y Franklin CL Reibarkh M Holmes MA Weinberg DH MacNeil T Tang R Tamvakopoulos C Peng Q Miller RR Stearns RA Chen HY Chen AS Strack AM Fong TM Wyvratt MJ Nargund RP 《Bioorganic & medicinal chemistry letters》2010,20(22):6524-6532
We report an SAR study of MC4R analogs containing spiroindane heterocyclic privileged structures. Compound 26 with N-Me-1,2,4-triazole moiety possesses exceptional potency at MC4R and potent anti-obesity efficacy in a mouse model. However, the efficacy is not completely mediated through MC4R. Additional SAR studies led to the discovery of compound 32, which is more potent at MC4R. Compound 32 demonstrates MC4R mediated anti-obesity efficacy in rodent models. 相似文献
65.
66.
Cep120 is asymmetrically localized to the daughter centriole and is essential for centriole assembly
Centrioles form the core of the centrosome in animal cells and function as basal bodies that nucleate and anchor cilia at the plasma membrane. In this paper, we report that Cep120 (Ccdc100), a protein previously shown to be involved in maintaining the neural progenitor pool in mouse brain, is associated with centriole structure and function. Cep120 is up-regulated sevenfold during differentiation of mouse tracheal epithelial cells (MTECs) and localizes to basal bodies. Cep120 localizes preferentially to the daughter centriole in cycling cells, and this asymmetry between mother and daughter centrioles is relieved coincident with new centriole assembly. Photobleaching recovery analysis identifies two pools of Cep120, differing in their halftime at the centriole. We find that Cep120 is required for centriole duplication in cycling cells, centriole amplification in MTECs, and centriole overduplication in S phase-arrested cells. We propose that Cep120 is required for centriole assembly and that the observed defect in neuronal migration might derive from a defect in this process. 相似文献
67.
Human beta3 adrenergic receptor agonists containing cyclic ureidobenzenesulfonamides 总被引:1,自引:0,他引:1
Parmee ER Naylor EM Perkins L Colandrea VJ Ok HO Candelore MR Cascieri MA Deng L Feeney WP Forrest MJ Hom GJ MacIntyre DE Miller RR Stearns RA Strader CD Tota L Wyvratt MJ Fisher MH Weber AE 《Bioorganic & medicinal chemistry letters》1999,9(5):749-754
Human beta3 adrenergic receptor agonists containing 5-membered ring ureas were shown to be potent partial agonists with excellent selectivity over beta1 and beta2 binding. L-760,087 (4a) and L-764,646 (5a) (beta3 EC50 = 18 and 14 nM, respectively) stimulate lipolysis in rhesus monkeys (ED50 = 0.2 and 0.1 mg/kg, respectively) with minimal effects on heart rate. Oral absorption in dogs is improved over other urea analogs. 相似文献
68.
69.
Lin LS Kopka IE Mumford RA Magriotis PA Lanza T Durette PL Kamenecka T Young DN de Laszlo SE McCauley E Riper GV Kidambi U Egger LA Tong X Lyons K Vincent S Stearns R Colletti A Teffera Y Fenyk-Melody J Schmidt JA MacCoss M Hagmann WK 《Bioorganic & medicinal chemistry letters》2002,12(4):611-614
Acylated beta-amino acids are described as potent, specific and orally bioavailable antagonists of VLA-4. The initial lead was identified from a combinatorial library. Subsequent optimization using a traditional medicinal chemistry approach led to significant improvement in potency (up to 8-fold) while maintaining good pharmacokinetic properties. 相似文献
70.
The Mammalian γ-Tubulin Complex Contains Homologues of the Yeast Spindle Pole Body Components Spc97p and Spc98p
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γ-Tubulin is a universal component of microtubule organizing centers where it is believed to play an important role in the nucleation of microtubule polymerization. γ-Tubulin also exists as part of a cytoplasmic complex whose size and complexity varies in different organisms. To investigate the composition of the cytoplasmic γ-tubulin complex in mammalian cells, cell lines stably expressing epitope-tagged versions of human γ-tubulin were made. The epitope-tagged γ-tubulins expressed in these cells localize to the centrosome and are incorporated into the cytoplasmic γ-tubulin complex. Immunoprecipitation of this complex identifies at least seven proteins, with calculated molecular weights of 48, 71, 76, 100, 101, 128, and 211 kD. We have identified the 100- and 101-kD components of the γ-tubulin complex as homologues of the yeast spindle pole body proteins Spc97p and Spc98p, and named the corresponding human proteins hGCP2 and hGCP3. Sequence analysis revealed that these proteins are not only related to their respective homologues, but are also related to each other. GCP2 and GCP3 colocalize with γ-tubulin at the centrosome, cosediment with γ-tubulin in sucrose gradients, and coimmunoprecipitate with γ-tubulin, indicating that they are part of the γ-tubulin complex. The conservation of a complex involving γ-tubulin, GCP2, and GCP3 from yeast to mammals suggests that structurally diverse microtubule organizing centers such as the yeast spindle pole body and the animal centrosome share a common molecular mechanism for microtubule nucleation. 相似文献