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Articles 31 - 38 of 38
Full-Text Articles in Enzymes and Coenzymes
Mechanism Underlying Ikk Activation Mediated By The Linear Ubiquitin Chain Assembly Complex (Lubac), Hiroaki Fujita, Simin Rahighi, Mariko Akita, Ryuichi Kato, Yoshiteru Sasaki, Soichi Wakatsuki, Kazuhiro Iwai
Mechanism Underlying Ikk Activation Mediated By The Linear Ubiquitin Chain Assembly Complex (Lubac), Hiroaki Fujita, Simin Rahighi, Mariko Akita, Ryuichi Kato, Yoshiteru Sasaki, Soichi Wakatsuki, Kazuhiro Iwai
Pharmacy Faculty Articles and Research
The linear ubiquitin chain assembly complex (LUBAC) ligase, consisting of HOIL-1L, HOIP, and SHARPIN, specifically generates linear polyubiquitin chains. LUBAC-mediated linear polyubiquitination has been implicated in NF-κB activation. NEMO, a component of the IκB kinase (IKK) complex, is a substrate of LUBAC, but the precise molecular mechanism underlying linear chain-mediated NF-κB activation has not been fully elucidated. Here, we demonstrate that linearly polyubiquitinated NEMO activates IKK more potently than unanchored linear chains. In mutational analyses based on the crystal structure of the complex between the HOIP NZF1 and NEMO CC2-LZ domains, which are involved in the HOIP-NEMO interaction, NEMO mutations …
Synthesis And Evaluation Of C-Src Kinase Inhibitory Activity Of Pyridin-2(1h)-One Derivatives, Karam Chand, Suchita Prasad, Rakesh Tiwari, Amir Nasrolahi Shirazi, Sumit Kumar, Keykavous Parang, Sunil K. Sharma
Synthesis And Evaluation Of C-Src Kinase Inhibitory Activity Of Pyridin-2(1h)-One Derivatives, Karam Chand, Suchita Prasad, Rakesh Tiwari, Amir Nasrolahi Shirazi, Sumit Kumar, Keykavous Parang, Sunil K. Sharma
Pharmacy Faculty Articles and Research
Src kinase, a prototype member of the Src family of kinases (SFKs), is over-expressed in various human tumors, and has become a target for anticancer drug design. In this perspective, a series of eighteen 2-pyridone derivatives were synthesized and evaluated for their c-Src kinase inhibitory activity. Among them, eight compounds exhibited c-Src kinase inhibitory activity with IC50 value of less than 25 mu M. Compound 1-[2-(dimethylamino)ethyl]-5-(2-hydroxy-4-methoxybenzoyl)pyridin-2(1H)-one (36) exhibited the highest c-Src kinase inhibition with an IC50 value of 12.5 mu M. Furthermore, the kinase inhibitory activity of compound 36 was studied against EGFR, MAPK and PDK, however no significant activity …
Structure-Functional Prediction And Analysis Of Cancer Mutation Effects In Protein Kinases, Anshuman Dixit, Gennady M. Verkhivker
Structure-Functional Prediction And Analysis Of Cancer Mutation Effects In Protein Kinases, Anshuman Dixit, Gennady M. Verkhivker
Mathematics, Physics, and Computer Science Faculty Articles and Research
A central goal of cancer research is to discover and characterize the functional effects of mutated genes that contribute to tumorigenesis. In this study, we provide a detailed structural classification and analysis of functional dynamics for members of protein kinase families that are known to harbor cancer mutations. We also present a systematic computational analysis that combines sequence and structure-based prediction models to characterize the effect of cancer mutations in protein kinases. We focus on the differential effects of activating point mutations that increase protein kinase activity and kinase-inactivating mutations that decrease activity. Mapping of cancer mutations onto the conformational …
Synthesis Of Pyrazolo[3,4-D]Pyrimidine Derivatives And Evaluation Of Their Src Kinase Inhibitory Activities, Anil Kumar, Guofeng Ye, Xianfeng Gu, Yuehao Wang, Gongqin Sun, Keykavous Parang
Synthesis Of Pyrazolo[3,4-D]Pyrimidine Derivatives And Evaluation Of Their Src Kinase Inhibitory Activities, Anil Kumar, Guofeng Ye, Xianfeng Gu, Yuehao Wang, Gongqin Sun, Keykavous Parang
Pharmacy Faculty Articles and Research
A series of pyrazolo[3,4-d]pyrimidine derivatives was synthesized and evaluated for the Src kinase inhibitory activities. Compound 6e and 10c exhibited inhibition of Src kinase with an IC50 value of 5.6 and 5.1 μM, respectively. Hydroxamate derivative 15a was found to be a metal-mediated inhibitor for human Csk with an IC50 value of 2.0 μM showing 56-fold selectivity over Src kinase inhibition.
Selectivity Of The Ubiquitin-Binding Modules, Simin Rahighi, Ivan Dikic
Selectivity Of The Ubiquitin-Binding Modules, Simin Rahighi, Ivan Dikic
Pharmacy Faculty Articles and Research
Ubiquitin-binding modules are constituents of cellular proteins that mediate the effects of ubiquitylation by making transient, non-covalent interactions with ubiquitin molecules. While some ubiquitin- binding modules bind single ubiquitin moieties, others are selective for specific ubiquitin chains of different linkage types and lengths. In recent years, functions of ubiquitin chains that are polymerized through their Lys or N-terminal Met (i.e. linear chains) residues have been linked to a variety of cellular processes. Selectivity of ubiquitin-binding modules for different ubiquitin chain types appears as a key to the distinct regulatory consequences during protein quality control pathways, receptor endocytosis, gene transcription, signaling …
Substituted Coumarin Derivatives: Synthesis And Evaluation Of Antiproliferative And Src Kinase Inhibitory Activities, Abha Kathuria, Sarah Jalal, Rakesh Tiwari, Amir Nasrolahi Shirazi, Shilpi Gupta, Shiv Kumar, Keykavous Parang, Sunil K. Sharma
Substituted Coumarin Derivatives: Synthesis And Evaluation Of Antiproliferative And Src Kinase Inhibitory Activities, Abha Kathuria, Sarah Jalal, Rakesh Tiwari, Amir Nasrolahi Shirazi, Shilpi Gupta, Shiv Kumar, Keykavous Parang, Sunil K. Sharma
Pharmacy Faculty Articles and Research
Six classes of coumarin derivatives (i.e. 3-alkyl-4-methylcoumarins, pyranocoumarins, coumarin carboxamides, quaternary ammonium coumarins, 7-aminocoumarins, and 4-aminocoumarins) were synthesized and evaluated for inhibition of cell proliferation of colon adenocarcinoma (HT-29), breast carcinoma (MDA-MB-468 or MCF-7), and human ovarian adenocarcinoma (SK-OV-3) cells. C-3-Alkyl substituted analogs of 4-methylcoumarins and pyranocoumarins, 5 and 6, inhibited the cell proliferation of MDA-MB-468 and SK-OV-3 cells by 53-74%, while 3-decyl substituted pyranocoumarin 10 and triethyl substituted quaternary ammonium coumarin derivative 29 inhibited the cell proliferation of HT-29 and SK-OV-3 cells by 63-72% at a concentration of 50 μM. Among all the compounds studied, C-3 decyl substituted quaternary …
Enzymatic Processing Of Amelogenin During Continuous Crystallization Of Apatite, Vuk Uskoković, M.-K. Kim, W. Li, S. Habelitz
Enzymatic Processing Of Amelogenin During Continuous Crystallization Of Apatite, Vuk Uskoković, M.-K. Kim, W. Li, S. Habelitz
Pharmacy Faculty Articles and Research
Dental enamel forms through a protein-controlled mineralization and enzymatic degradation with a nanoscale precision that new engineering technologies may be able to mimic. Recombinant fulllength human amelogenin (rH174) and a matrix-metalloprotease (MMP-20) were employed in a pHstat titration system that enabled a continuous supply of calcium and phosphate ions over several days, mimicking the initial stages of matrix processing and crystallization in enamel in-vitro. Effects on the self-assembly and crystal growth from a saturated aqueous solution containing 0.4 mg/ml rH174 and MMP-20 with the weight ratio of 1:1000 with respect to rH174 were investigated. A transition from nanospheres to fibrous …
Novel Approaches For Designing 5'-O-Ester Prodrugs Of 3'-Azido-2'3'-Dideoxythymidine (Azt), Keykavous Parang, Leonard I. Wiebe, Edward E. Knaus
Novel Approaches For Designing 5'-O-Ester Prodrugs Of 3'-Azido-2'3'-Dideoxythymidine (Azt), Keykavous Parang, Leonard I. Wiebe, Edward E. Knaus
Pharmacy Faculty Articles and Research
3'-Azido-2'3'-dideoxythymidine (AZT, 1, zidovudine, RetrovirTM) is used to treat patients with human immunodeficiency virus (HIV) infection. AZT, after conversion to AZT-5'-triphosphate (AZT-TP) by cellular enzymes, inhibits HIV-reverse transcriptase (HIV-RT). The major clinical limitations of AZT are due to clinical toxicities that include bone marrow suppression, hepatic abnormalities and myopathy, absolute dependence on host cell kinase-mediated activation which leads to low activity, limited brain uptake, a sort half-life of about one hour in plasma that dictates frequent administration to maintain therapeutic drug levels, low potential for metabolic activation and/or high susceptibility to catabolism, and the rapid development of resistance by HIV-1. …