Kinase drug discovery 20 years after imatinib: progress and future directions

Nature Reviews Drug Discovery, Journal Year: 2021, Volume and Issue: 20(7), P. 551 - 569

Published: May 17, 2021

Language: Английский

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The target landscape of clinical kinase drugs

Science, Journal Year: 2017, Volume and Issue: 358(6367)

Published: Nov. 30, 2017

Kinase inhibitors are important cancer therapeutics. Polypharmacology is commonly observed, requiring thorough target deconvolution to understand drug mechanism of action. Using chemical proteomics, we analyzed the spectrum 243 clinically evaluated kinase drugs. The data revealed previously unknown targets for established drugs, offered a perspective on "druggable" kinome, highlighted (non)kinase off-targets, and suggested potential therapeutic applications. Integration phosphoproteomic refined drug-affected pathways, identified response markers, strengthened rationale combination treatments. We exemplify translational value by discovering SIK2 (salt-inducible 2) that modulate cytokine production in primary cells, identifying drugs against lung survival marker MELK (maternal embryonic leucine zipper kinase), repurposing cabozantinib treat FLT3-ITD-positive acute myeloid leukemia. This resource, available via ProteomicsDB database, should facilitate basic, clinical, discovery research aid clinical decision-making.

Language: Английский

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Parkin is activated by PINK1-dependent phosphorylation of ubiquitin at Ser65

Biochemical Journal, Journal Year: 2014, Volume and Issue: 460(1), P. 127 - 141

Published: March 25, 2014

We have previously reported that the Parkinson's disease-associated kinase PINK1 (PTEN-induced putative 1) is activated by mitochondrial depolarization and stimulates Parkin E3 ligase phosphorylating Ser65 within its Ubl (ubiquitin-like) domain. Using phosphoproteomic analysis, we identified a novel ubiquitin phosphopeptide phosphorylated at was enriched 14-fold in HEK (human embryonic kidney)-293 cells overexpressing wild-type stimulated with uncoupling agent CCCP (carbonyl cyanide m-chlorophenylhydrazone), to activate PINK1, compared expressing kinase-inactive PINK1. lies similar motif domain of Parkin. Remarkably, directly phosphorylates vitro. undertook series experiments provide striking evidence Ser65-phosphorylated (ubiquitinPhospho-Ser65) functions as critical activator First, demonstrate fragment lacking encompassing (ΔUbl-Parkin) robustly ubiquitinPhospho-Ser65, but not non-phosphorylated ubiquitin. Secondly, find isolated (UblPhospho-Ser65) can also ΔUbl-Parkin similarly ubiquitinPhospho-Ser65. Thirdly, establish or UblPhospho-Ser65, activates full-length well non-phosphorylatable S65A mutant. Fourthly, optimal activation dependent on PINK1-mediated phosphorylation both Ser65, since only mutation proteins completely abolishes activation. In conclusion, findings present study reveal controls activity Ser65. propose serves prime enzyme for suggesting small molecules mimic ubiquitinPhospho-Ser65 could hold promise therapies disease.

Language: Английский

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Targeting the translation machinery in cancer

Nature Reviews Drug Discovery, Journal Year: 2015, Volume and Issue: 14(4), P. 261 - 278

Published: March 6, 2015

Language: Английский

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The RSK family of kinases: emerging roles in cellular signalling

Nature Reviews Molecular Cell Biology, Journal Year: 2008, Volume and Issue: 9(10), P. 747 - 758

Published: Sept. 29, 2008

Language: Английский

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Bifurcation of insulin signaling pathway in rat liver: mTORC1 required for stimulation of lipogenesis, but not inhibition of gluconeogenesis

Proceedings of the National Academy of Sciences, Journal Year: 2010, Volume and Issue: 107(8), P. 3441 - 3446

Published: Feb. 1, 2010

The livers of insulin-resistant, diabetic mice manifest selective insulin resistance, suggesting a bifurcation in the signaling pathway: Insulin loses its ability to block glucose production (i.e., it fails suppress PEPCK and other genes gluconeogenesis), yet retains stimulate fatty acid synthesis continued enhancement lipogenesis). Enhanced lipogenesis is accompanied by an insulin-stimulated increase mRNA encoding SREBP-1c, transcription factor that activates entire lipogenic program. Here, we report branch point pathway may account for resistance. Exposure rat hepatocytes produced 25-fold SREBP-1c 95% decrease mRNA. Insulin-mediated changes both mRNAs were blocked inhibitors PI3K Akt, indicating these kinases are required pathways. In contrast, subnanomolar concentrations rapamycin, inhibitor mTORC1 kinase, induction , but had no effect on suppression . We observed similar rapamycin rats experienced surge response fasting-refeeding protocol. A specific S6 downstream target mTORC1, did not distinct from kinase. These results establish as essential component insulin-regulated hepatic gluconeogenesis, help resolve paradox resistance rodents.

Language: Английский

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Mitogen-Activated Protein Kinase Signaling in the Heart: Angels Versus Demons in a Heart-Breaking Tale

Physiological Reviews, Journal Year: 2010, Volume and Issue: 90(4), P. 1507 - 1546

Published: Oct. 1, 2010

Among the myriad of intracellular signaling networks that govern cardiac development and pathogenesis, mitogen-activated protein kinases (MAPKs) are prominent players have been focus extensive investigations in past decades. The four best characterized MAPK subfamilies, ERK1/2, JNK, p38, ERK5, targets pharmacological genetic manipulations to uncover their roles development, function, diseases. However, information reported literature from these efforts has not yet resulted a clear view about specific pathways heart. Rather, controversies contradictive results led perception MAPKs ambiguous characters heart with both protective detrimental effects. primary object this review is provide comprehensive overview current progress, an effort highlight areas where consensus established verses ones controversy remains. hypertrophy, ischemia/reperfusion injury, pathological remodeling main focuses as represent most critical issues for evaluating viable therapeutic development. studies presented will help reveal major challenges field limitations approaches point need future gain better understanding fundamental mechanisms function regulation

Language: Английский

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Hypoxic Pulmonary Vasoconstriction

Physiological Reviews, Journal Year: 2012, Volume and Issue: 92(1), P. 367 - 520

Published: Jan. 1, 2012

It has been known for more than 60 years, and suspected over 100, that alveolar hypoxia causes pulmonary vasoconstriction by means of mechanisms local to the lung. For last 20 it clear essential sensor, transduction, effector responsible hypoxic (HPV) reside in arterial smooth muscle cell. The main focus this review is cellular molecular work performed clarify these intrinsic determine how they are facilitated inhibited extrinsic influences other cells. Because interaction likely shape expression HPV vivo, we relate results obtained cells intact preparations, such as isolated lungs vessels. Finally, evaluate evidence regarding contribution physiological pathophysiological processes involved transition from fetal neonatal life, gas exchange, high-altitude edema, hypertension. Although understanding advanced significantly, major areas ignorance uncertainty await resolution.

Language: Английский

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Targeting the cancer kinome through polypharmacology

Nature reviews. Cancer, Journal Year: 2010, Volume and Issue: 10(2), P. 130 - 137

Published: Jan. 22, 2010

Language: Английский

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Tyrosine phosphorylation: thirty years and counting

Current Opinion in Cell Biology, Journal Year: 2009, Volume and Issue: 21(2), P. 140 - 146

Published: March 10, 2009

Language: Английский

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