Hepatic Metabolism of MK-0457, a Potent Aurora Kinase Inhibitor: Interspecies Comparison and Role of Human Cytochrome P450 and Flavin-Containing Monooxygenase

2007 ◽  
Vol 35 (9) ◽  
pp. 1447-1451 ◽  
Author(s):  
J. E. Ballard ◽  
T. Prueksaritanont ◽  
C. Tang
Keyword(s):  
Cytochrome P450 ◽  
Kinase Inhibitor ◽  
Hepatic Metabolism ◽  
Aurora Kinase ◽  
Aurora Kinase Inhibitor ◽  
Interspecies Comparison ◽  
Human Cytochrome

scholarly journals Inhibitors of Signaling Pathways That Block Reversal of HIV-1 Latency

2018 ◽  
Vol 63 (2) ◽  
pp. e01744-18 ◽  
Author(s):  
Benni Vargas ◽  
Nicholas S. Giacobbi ◽  
Anwesha Sanyal ◽  
Narasimhan J. Venkatachari ◽  
Feng Han ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Aurora Kinase ◽  
Aurora Kinase Inhibitor ◽  
Kinase C ◽  
Wide Range ◽  
Latent Hiv ◽  
Hiv 1

ABSTRACT Signaling pathways play a key role in HIV-1 latency. In this study, we used the 24ST1NLESG cell line of HIV-1 latency to screen a library of structurally diverse, medicinally active, cell permeable kinase inhibitors, which target a wide range of signaling pathways, to identify inhibitors of HIV-1 latency reversal. The screen was carried out in the absence or presence of three mechanistically distinct latency-reversing agents (LRAs), namely, prostratin, panobinostat, and JQ-1. We identified inhibitors that only blocked the activity of a specific LRA, as well as inhibitors that blocked the activity of all LRAs. For example, we identified 12 inhibitors targeted toward protein kinase C or downstream kinases that blocked the activity of prostratin. We also identified 12 kinase inhibitors that blocked the reversal of HIV-1 latency irrespective of the LRA used in the screen. Of these, danusertib, an Aurora kinase inhibitor, and PF-3758309, a PAK4 inhibitor, were the most potent. The 50% inhibitory concentrations in the 24ST1NLESG cells ranged from 40 to 147 nM for danusertib (selectivity indices, >150) and from 0.1 to 1 nM for PF-3758309 (selectivity indices, >3,300). Both danusertib and PF-3758309 inhibited latency reversal in CD4+ T cells isolated from HIV-1-infected donors. Collectively, our study describes a chemical approach that can be applied to elucidate the role of signaling pathways involved in LRA activity or the maintenance of HIV-1 latency and also identifies inhibitors of latent HIV-1 reactivation that could be used with antiretroviral therapy to reduce residual viremia.

scholarly journals Role of the ABCG2 drug transporter in the resistance and oral bioavailability of a potent cyclin-dependent kinase/Aurora kinase inhibitor

2006 ◽  
Vol 5 (10) ◽  
pp. 2459-2467 ◽  
Author(s):  
Jennifer A. Seamon ◽  
Catherine A. Rugg ◽  
Stuart Emanuel ◽  
Anna Maria Calcagno ◽  
Suresh V. Ambudkar ◽  
...  
Keyword(s):  
Oral Bioavailability ◽  
Kinase Inhibitor ◽  
Aurora Kinase ◽  
Drug Transporter ◽  
Cyclin Dependent Kinase ◽  
Aurora Kinase Inhibitor

scholarly journals Pathways of Carbamazepine Bioactivation in Vitro. III. The Role of Human Cytochrome P450 Enzymes in the Formation of 2,3-Dihydroxycarbamazepine

2008 ◽  
Vol 36 (8) ◽  
pp. 1637-1649 ◽  
Author(s):  
Robin E. Pearce ◽  
Wei Lu ◽  
YongQiang Wang ◽  
Jack P. Uetrecht ◽  
Maria Almira Correia ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Cytochrome P450 Enzymes ◽  
Human Cytochrome

scholarly journals The human Aurora kinase inhibitor danusertib is a lead compound for anti-trypanosomal drug discovery via target repurposing

2013 ◽  
Vol 62 ◽  
pp. 777-784 ◽  
Author(s):  
Stefan O. Ochiana ◽  
Vidya Pandarinath ◽  
Zhouxi Wang ◽  
Rishika Kapoor ◽  
Mary Jo Ondrechen ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Kinase Inhibitor ◽  
Aurora Kinase ◽  
Lead Compound ◽  
Aurora Kinase Inhibitor ◽  
Target Repurposing

A phase l study of three different dosing schedules of the oral aurora kinase inhibitor MSC1992371A in patients with solid tumors

2013 ◽  
Vol 9 (3) ◽  
pp. 215-224 ◽  
Author(s):  
M. Mita ◽  
M. Gordon ◽  
N. Rejeb ◽  
A. Gianella-Borradori ◽  
V. Jego ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Kinase Inhibitor ◽  
Aurora Kinase ◽  
Aurora Kinase Inhibitor

scholarly journals Aurora kinases A and B are up-regulated by Myc and are essential for maintenance of the malignant state

Blood ◽  
2010 ◽  
Vol 116 (9) ◽  
pp. 1498-1505 ◽  
Author(s):  
Jürgen den Hollander ◽  
Sara Rimpi ◽  
Joanne R. Doherty ◽  
Martina Rudelius ◽  
Andreas Buck ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Kinase Activity ◽  
Kinase Inhibitor ◽  
Aurora Kinase ◽  
Cell Cycle Regulators ◽  
Aurora Kinase Inhibitor ◽  
Aurora Kinases ◽  
Protein Levels ◽  
Malignant State ◽  
E Boxes

Myc oncoproteins promote continuous cell growth, in part by controlling the transcription of key cell cycle regulators. Here, we report that c-Myc regulates the expression of Aurora A and B kinases (Aurka and Aurkb), and that Aurka and Aurkb transcripts and protein levels are highly elevated in Myc-driven B-cell lymphomas in both mice and humans. The induction of Aurka by Myc is transcriptional and is directly mediated via E-boxes, whereas Aurkb is regulated indirectly. Blocking Aurka/b kinase activity with a selective Aurora kinase inhibitor triggers transient mitotic arrest, polyploidization, and apoptosis of Myc-induced lymphomas. These phenotypes are selectively bypassed by a kinase inhibitor-resistant Aurkb mutant, demonstrating that Aurkb is the primary therapeutic target in the context of Myc. Importantly, apoptosis provoked by Aurk inhibition was p53 independent, suggesting that Aurka/Aurkb inhibitors will show efficacy in treating primary or relapsed malignancies having Myc involvement and/or loss of p53 function.

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