排序方式: 共有26条查询结果,搜索用时 31 毫秒
1.
Zificsak CA Gingrich DE Breslin HJ Dunn DD Milkiewicz KL Theroff JP Thieu TV Underiner TL Weinberg LR Aimone LD Albom MS Mason JL Saville L Husten J Angeles TS Finn JP Jan M O'Kane TM Dobrzanski P Dorsey BD 《Bioorganic & medicinal chemistry letters》2012,22(1):133-137
The elaboration of a novel scaffold for the inhibition of JAK2 and FAK kinases was targeted in order to provide a dual inhibitor that could target divergent pathways for tumor cell progression. 相似文献
2.
Underiner TL Ruggeri B Aimone L Albom M Angeles T Chang H Hudkins RL Hunter K Josef K Robinson C Weinberg L Yang S Zulli A 《Bioorganic & medicinal chemistry letters》2008,18(7):2368-2372
Orally bioavailable, dual inhibitors of TIE-2/VEGF-R2 were identified by elaborating the C3/N13 SAR around a fused pyrrolodihydroindazolocarbazole scaffold. Analogs bearing a C3-thiophencarbonyl group were evaluated in enzymatic and cellular biochemical assays; two orally bioavailable analogs were further profiled in functional assays and found to inhibit microvessel growth in rat aortic explant cultures and inhibit Ang-1-stimulated chemotaxis of HUVECs. 相似文献
3.
Background
Protein translocation across the membrane of the Endoplasmic Reticulum (ER) is the first step in the biogenesis of secretory and membrane proteins. Proteins enter the ER by the Sec61 translocon, a proteinaceous channel composed of three subunits, α, β and γ. While it is known that Sec61α forms the actual channel, the function of the other two subunits remains to be characterized.Results
In the present study we have investigated the function of Sec61β in Drosophila melanogaster. We describe its role in the plasma membrane traffic of Gurken, the ligand for the Epidermal Growth Factor (EGF) receptor in the oocyte. Germline clones of the mutant allele of Sec61β show normal translocation of Gurken into the ER and transport to the Golgi complex, but further traffic to the plasma membrane is impeded. The defect in plasma membrane traffic due to absence of Sec61β is specific for Gurken and is not due to a general trafficking defect.Conclusion
Based on our study we conclude that Sec61β, which is part of the ER protein translocation channel affects a post-ER step during Gurken trafficking to the plasma membrane. We propose an additional role of Sec61β beyond protein translocation into the ER. 相似文献4.
Sequence of a cDNA for mouse thymidylate synthase reveals striking similarity with the prokaryotic enzyme 总被引:11,自引:0,他引:11
Perryman SM; Rossana C; Deng TL; Vanin EF; Johnson LF 《Molecular biology and evolution》1986,3(4):313-321
We report the nucleotide sequence of a cloned cDNA, pMTS-3, that contains a
1-kb insert corresponding to mouse thymidylate synthase (E.C. 2.1.1.45).
The open reading frame of 921 nucleotides from the first AUG to the
termination codon specifies a protein with a molecular mass of 34,962
daltons. The predicted amino acid sequence is 90% identical with that of
the human enzyme. The mouse sequence also has an extremely high degree of
similarity (as much as 55% identity) with prokaryotic thymidylate synthase
sequences, indicating that thymidylate synthase is among the most highly
conserved proteins studied to date. The similarity is especially pronounced
(as much as 80% identity) in the 44-amino-acid region encompassing the
binding site for deoxyuridylic acid. The cDNA sequence also suggests that
mouse thymidylate synthase mRNA lacks a 3' untranslated region, since the
termination codon, UAA, is followed immediately by a poly(A) segment.
相似文献
5.
Weinberg LR Albom MS Angeles TS Breslin HJ Gingrich DE Huang Z Lisko JG Mason JL Milkiewicz KL Thieu TV Underiner TL Wells GJ Wells-Knecht KJ Dorsey BD 《Bioorganic & medicinal chemistry letters》2011,21(24):7325-7330
The JAK2/STAT pathway has important roles in hematopoiesis. With the discovery of the JAK2 V617F mutation and its presence in many patients with myeloproliferative neoplasms, research in the JAK2 inhibitor arena has dramatically increased. We report a novel series of potent JAK2 inhibitors containing a 2,7-pyrrolotriazine core. To minimize potential drug-induced toxicity, targets were analyzed for the ability to form a glutathione adduct. Glutathione adduct formation was decreased by modification of the aniline substituent at C2. 相似文献
6.
Zificsak CA Theroff JP Aimone LD Angeles TS Albom MS Cheng M Mesaros EF Ott GR Quail MR Underiner TL Wan W Dorsey BD 《Bioorganic & medicinal chemistry letters》2011,21(13):3877-3880
The incorporation of R,R-1,2-diaminocyclohexane at C4 in a series of 2,4-diaminopyrimidines led to a number of ALK inhibitors in which optimized activity was achieved by conversion of the 2-amino group into a methanesulfonamide. Tumor growth inhibition was observed when an orally bioavailable analog was evaluated in a Karpas-299 tumor xenograft mouse model. 相似文献
7.
Weinberg LR Albom MS Angeles TS Husten J Lisko JG McHugh RJ Milkiewicz KL Murthy S Ott GR Theroff JP Tripathy R Underiner TL Zificsak CA Dorsey BD 《Bioorganic & medicinal chemistry letters》2011,21(1):164-167
The HGF-c-Met signaling axis is an important paracrine mediator of epithelial-mesenchymal cell interactions involving the regulation of multiple cellular activities including cell motility, mitogenesis, morphogenesis, and angiogenesis. Dysregulation of c-Met signaling (e.g., overexpression or increased activation) is associated with the development of a wide range of tumor types; thus, inhibiting the HGF-c-Met pathway is predicted to lead to anti-tumor effects in many cancers. Elaboration of a 2-arylaminopyrimidine scaffold led to a series of potent c-Met inhibitors bearing a C4-2-amino-N-methylbenzamide group. Specifically, a series of C2-benzazepinone analogs demonstrated potent inhibition of c-Met in enzymatic and cellular assays. Kinase selectivity could be tuned by varying the nature of the alkyl group on the benzazepinone nitrogen. 相似文献
8.
Dandu R Zulli AL Bacon ER Underiner T Robinson C Chang H Miknyoczki S Grobelny J Ruggeri BA Yang S Albom MS Angeles TS Aimone LD Hudkins RL 《Bioorganic & medicinal chemistry letters》2008,18(6):1916-1921
Fused dihydroindazolopyrrolocarbazole oximes have been identified as low nanomolar, potent dual TIE-2 and VEGF-R2 receptor tyrosine kinase inhibitors with excellent cellular potency. Development of the structure-activity relationships (SAR) led to identification of compounds 35 and 40 as potent, selective dual TIE-2/VEGF-R2 inhibitors with favorable pharmacokinetic properties. Compound 35 was orally active in tumor models with no observed toxicity. 相似文献
9.
10.
Role of the reticulum in the stability and shape of the isolated human erythrocyte membrane 总被引:12,自引:7,他引:5 下载免费PDF全文
In order to examine the widely held hypothesis that the reticulum of proteins which covers the cytoplamsic surface of the human erythrocyte membrane controls cell stability and shape, we have assessed some of its properties. The reticulum, freed of the bilayer by extraction with Triton X-100, was found to be mechanically stable at physiological ionic strength but physically unstable at low ionic strength. The reticulum broke down after a characteristic lag period which decreased 500-fold between 0 degrees and 37 degrees C. The release of polypeptide band 4.1 from the reticulum preceded that of spectrin and actin, suggesting that band 4.1 might stabilize the ensemble but is not essential to its integrity. The time-course of breakdown was similar for ghosts, the reticulum inside of ghosts, and the isolated reticulum. However, at very low ionic strength, the reticulum was less stable within the ghost than when free; at higher ionic strength, the reverse was true. Over a wide range of conditions the membrane broke down to vesicles just as the reticulum disintegrated, presumably because the bilayer was mechanically stabilized by this network. The volume of both ghosts and naked reticula varied inversely and reversibly with ionic strength. The volume of the naked reticulum varied far more widely than the ghost, suggesting that its deformation was normally limited by the less extensible bilayer. The contour of the isolated reticulum was discoid and often dimpled or indented, as visualized in the fluorescence microscope after labeling of the ghosts with fluoroscein isothiocyanate. Reticula derived from ghosts which had lost the ability to crenate in isotonic saline were shriveled, even though the bilayer was smooth and expanded. Conversly, ghosts crenated by dinitrophenol yielded smooth, expanded reticula. We conclude that the reticulum is a durable, flexible, and elastic network which assumes and stabilizes the contour of the membrane but is not responsible for its crenation. 相似文献