scholarly journals Design, Synthesis, and Biochemical Evaluation of New Triazole Derivatives as Aurora-A Kinase Inhibitors

Molecules ◽  
2021 ◽  
Vol 26 (18) ◽  
pp. 5678
Author(s):  
Omeima Abdullah
Keyword(s):  
Kinase Inhibitors ◽  
Dependent Manner ◽  
Aurora A Kinase ◽  
Aurora A ◽  
Design Synthesis ◽  
Triazole Derivatives ◽  
Pancreatic Cancers ◽  
A Cell ◽  
Cycle Dependent ◽  
New Compounds

Aurora-A kinase, a key mitosis regulator, is expressed in a cell cycle-dependent manner and has an essential role in maintaining chromosomal stability and the normal progression of the cell through mitosis. Aurora-A kinase is overexpressed in many malignant solid tumors, such as breast, ovarian, colon, and pancreatic cancers. Thus, inhibiting Aurora-A kinase activity is a promising approach for cancer treatment. Here, new triazole derivatives were designed as bioisosteric analogues of the known inhibitor JNJ-7706621. The new compounds showed interesting inhibitory activity against Aurora-A kinase, as attested by IC50s in the low to submicromolar range.

Design, synthesis and bioevaluation of N-trisubstituted pyrimidine derivatives as potent aurora A kinase inhibitors

2014 ◽  
Vol 78 ◽  
pp. 65-71 ◽  
Author(s):  
Yu Luo ◽  
Yan-Qiu Deng ◽  
Jing Wang ◽  
Zi-Jie Long ◽  
Zheng-Chao Tu ◽  
...  
Keyword(s):  
Kinase Inhibitors ◽  
Aurora A Kinase ◽  
Aurora A ◽  
Pyrimidine Derivatives ◽  
Design Synthesis

scholarly journals Truncated APC regulates the transcriptional activity of β-catenin in a cell cycle dependent manner

2006 ◽  
Vol 16 (2) ◽  
pp. 199-209 ◽  
Author(s):  
Jean Schneikert ◽  
Annette Grohmann ◽  
Jürgen Behrens
Keyword(s):  
Cell Cycle ◽  
Transcriptional Activity ◽  
Dependent Manner ◽  
A Cell ◽  
Cycle Dependent

Structural models for the self-assembly and microtubule interactions of gamma-, delta- and epsilon-tubulin

2001 ◽  
Vol 114 (2) ◽  
pp. 413-422 ◽  
Author(s):  
Y.F. Inclan ◽  
E. Nogales
Keyword(s):  
Self Assembly ◽  
Structural Models ◽  
Dependent Manner ◽  
Gamma Delta ◽  
Sequence Comparisons ◽  
Alpha Tubulin ◽  
A Cell ◽  
Gamma Tubulin ◽  
Cycle Dependent ◽  
Key Residues

alphabeta-tubulin heterodimers self-assemble to form microtubules nucleated by gamma-tubulin in the cell. Gamma-tubulin is believed to recruit the alphabeta-tubulin dimers that form the minus ends of microtubules, but the molecular mechanism of this action remains a matter of heated controversy. Still less is known about the function and molecular interactions of delta-tubulin and epsilon-tubulin. delta-tubulin may seed the formation of the C triplet tubules in the basal bodies of Chlamydomonas and epsilon-tubulin is known to localize to the centrosome in a cell cycle-dependent manner. Using the structure of alphabeta tubulin as a model, we have analyzed the sequences of gamma-, delta- and epsilon-tubulin in regions corresponding to different polymerization interfaces in the tubulin alphabeta dimer. The sequence comparisons sometimes show clear conservation, pointing to similar types of contacts being functionally important for the new tubulin considered. Conversely, certain surfaces show marked differences that rule out equivalent interactions for non-microtubular tubulins. This sequence/structure analysis has led us to structural models of how these special tubulins may be involved in protein-protein contacts that affect microtubule self-assembly. delta-tubulin most likely interacts longitudinally with alpha-tubulin at the minus ends of microtubules, while epsilon-tubulin most likely binds to the plus end of beta-tubulin. Conservation of key residues in gamma-tubulin suggests that it is capable of longitudinal self-assembly. The implications for the protofilament and template models of nucleation are considered.

scholarly journals A Novel Cell-Based, High-Content Assay for Phosphorylation of Lats2 by Aurora A

2011 ◽  
Vol 16 (8) ◽  
pp. 925-931 ◽  
Author(s):  
Amy Emery ◽  
David A. Sorrell ◽  
Stacy Lawrence ◽  
Emma Easthope ◽  
Mark Stockdale ◽  
...  
Keyword(s):  
High Throughput ◽  
High Throughput Screening ◽  
Kinase Activity ◽  
High Content Screening ◽  
Aurora A Kinase ◽  
Aurora A ◽  
Assay Performance ◽  
A Cell ◽  
Significant Addition ◽  
Specific Inhibitors

Aurora A kinase is a key regulator of mitosis, which is upregulated in several human cancers, making it a potential target for anticancer therapeutics. Consequently, robust medium- to high-throughput cell-based assays to measure Aurora A kinase activity are critical for the development of small-molecule inhibitors. Here the authors compare measurement of the phosphorylation of two Aurora A substrates previously used in high-content screening Aurora A assays, Aurora A itself and TACC3, with a novel substrate Lats2. Using antibodies directed against phosphorylated forms of Aurora A (pThr288), P-TACC3 (pSer558), and P-Lats2 (pSer83), the authors investigate their suitability in parallel for development of a cell-based assay using several reference Aurora inhibitors: MLN8054, VX680, and AZD1152-HQPA. They validate a combined assay of target-specific phosphorylation of Lats2 at the centrosome and an increase in mitotic index as a measure of Aurora A activity. The assay is both sensitive and robust and has acceptable assay performance for high-throughput screening or potency estimation from concentration–response assays. It has the advantage that it can be carried out using a commercially available monoclonal antibody against phospho-Lats2 and the widely available Cellomics ArrayScan HCS reader and thus represents a significant addition to the tools available for the identification of Aurora A specific inhibitors.

scholarly journals Ser68 phosphoregulation is essential for CENP-A deposition, centromere function and viability in mice

2021 ◽  
Author(s):  
Yuting Liu ◽  
Kehui Wang ◽  
Li Huang ◽  
Jicheng Zhao ◽  
Xinpeng Chen ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Viability ◽  
Histone H3 ◽  
Dependent Manner ◽  
Centromere Function ◽  
Histone H3 Variant ◽  
A Cell ◽  
Cycle Dependent ◽  
Spatiotemporal Control

Centromere identity is defined by nucleosomes containing CENP-A, a histone H3 variant. The deposition of CENP-A at centromeres is tightly regulated in a cell-cycle-dependent manner. We previously reported that the spatiotemporal control of centromeric CENP-A incorporation is mediated by the phosphorylation of CENP-A Ser68. However, a recent report argued that Ser68 phosphoregulation is dispensable for accurate CENP-A loading. Here, we report that the substitution of Ser68 of endogenous CENP-A with either Gln68 or Glu68 severely impairs CENP-A deposition and cell viability. We also find that mice harboring the corresponding mutations are lethal. Together, these results indicate that the dynamic phosphorylation of Ser68 ensures cell-cycle-dependent CENP-A deposition and cell viability.

Benzo[e]pyrimido[5,4-b][1,4]diazepin-6(11H)-one derivatives as Aurora A kinase inhibitors: LQTA-QSAR analysis and detailed systematic validation of the developed model

2015 ◽  
Vol 19 (4) ◽  
pp. 965-974 ◽  
Author(s):  
Ashish M. Kanhed ◽  
Radha Charan Dash ◽  
Nishant Parmar ◽  
Tarun Kumar Das ◽  
Rajani Giridhar ◽  
...  
Keyword(s):  
Kinase Inhibitors ◽  
Aurora A Kinase ◽  
Aurora A ◽  
Qsar Analysis

ChemInform Abstract: Single Step Synthesis of New Fused Pyrimidine Derivatives and Their Evaluation as Potent Aurora-A Kinase Inhibitors.

ChemInform ◽  
2011 ◽  
Vol 43 (4) ◽  
pp. no-no
Author(s):  
Mohamed R. Shaaban ◽  
Tamer S. Saleh ◽  
Abdelrahman S. Mayhoub ◽  
Ahmad M. Farag
Keyword(s):  
Kinase Inhibitors ◽  
Single Step ◽  
Aurora A Kinase ◽  
Aurora A ◽  
Pyrimidine Derivatives

scholarly journals Gcn5-mediated acetylation at MBF-regulated promoters induces the G1/S transcriptional wave

2019 ◽  
Vol 47 (16) ◽  
pp. 8439-8451 ◽  
Author(s):  
Alberto González-Medina ◽  
Elena Hidalgo ◽  
José Ayté
Keyword(s):  
Cell Cycle ◽  
Molecular Mechanisms ◽  
Histone H3 ◽  
Dependent Manner ◽  
Saga Complex ◽  
Lysine Residues ◽  
Physical Barriers ◽  
A Cell ◽  
Cycle Dependent ◽  
Regulated Promoters

Abstract In fission yeast, MBF-dependent transcription is inactivated at the end of S phase through a negative feedback loop that involves the co-repressors, Yox1 and Nrm1. Although this repression system is well known, the molecular mechanisms involved in MBF activation remain largely unknown. Compacted chromatin constitutes a barrier to activators accessing promoters. Here, we show that chromatin regulation plays a key role in activating MBF-dependent transcription. Gcn5, a part of the SAGA complex, binds to MBF-regulated promoters through the MBF co-activator Rep2 in a cell cycle-dependent manner and in a reverse correlation to the binding of the MBF co-repressors, Nrm1 or Yox1. We propose that the co-repressors function as physical barriers to SAGA recruitment onto MBF promoters. We also show that Gcn5 acetylates specific lysine residues on histone H3 in a cell cycle-regulated manner. Furthermore, either in a gcn5 mutant or in a strain in which histone H3 is kept in an unacetylated form, MBF-dependent transcription is downregulated. In summary, Gcn5 is required for the full activation and correct timing of MBF-regulated gene transcription.

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