Development of a Highly Selective c-Src Kinase Inhibitor

Brandvold, Kristoffer R.; Steffey, Michael E.; Fox, Christel C.; Soellner, Matthew B.

doi:10.1021/cb300172e

Cited by 112 publications

(150 citation statements)

References 35 publications

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“…None of the effects was observed with PP3, a negative control for PP2. Recent studies reported that PP2 may inhibit other kinases with similar affinities and that it is less Src selective than the Src family kinase inhibitor dasatinib (Das) (4). Therefore, we also tested Das and found that it efficiently reduced FAK-p-Tyr…”

Section: Nrg1␤-induced Mtorc2-mediated Akt Phosphorylation At Sermentioning

confidence: 92%

Neuregulin-1β promotes glucose uptake via PI3K/Akt in neonatal rat cardiomyocytes

Pentassuglia

Heim

Lebboukh

et al. 2016

American Journal of Physiology-Endocrinology and Metabolism

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Nrg1β is critically involved in cardiac development and also maintains function of the adult heart. Studies conducted in animal models showed that it improves cardiac performance under a range of pathological conditions, which led to its introduction in clinical trials to treat heart failure. Recent work also implicated Nrg1β in the regenerative potential of neonatal and adult hearts. The molecular mechanisms whereby Nrg1β acts in cardiac cells are still poorly understood. In the present study, we analyzed the effects of Nrg1β on glucose uptake in neonatal rat ventricular myocytes and investigated to what extent mTOR/Akt signaling pathways are implicated. We show that Nrg1β enhances glucose uptake in cardiomyocytes as efficiently as IGF-I and insulin. Nrg1β causes phosphorylation of ErbB2 and ErbB4 and rapidly induces the phosphorylation of FAK (Tyr861), Akt (Thr308 and Ser473), and its effector AS160 (Thr642). Knockdown of ErbB2 or ErbB4 reduces Akt phosphorylation and blocks the glucose uptake. The Akt inhibitor VIII and the PI3K inhibitors LY-294002 and Byl-719 abolish Nrg1β-induced phosphorylation and glucose uptake. Finally, specific mTORC2 inactivation after knockdown of rictor blocks the Nrg1β-induced increases in Akt-p-Ser473 but does not modify AS160-p-Thr642 or the glucose uptake responses to Nrg1β. In conclusion, our study demonstrates that Nrg1β enhances glucose uptake in cardiomyocytes via ErbB2/ErbB4 heterodimers, PI3Kα, and Akt. Furthermore, although Nrg1β activates mTORC2, the resulting Akt-Ser473 phosphorylation is not essential for glucose uptake induction. These new insights into pathways whereby Nrg1β regulates glucose uptake in cardiomyocytes may contribute to the understanding of its regenerative capacity and protective function in heart failure.

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Section: Nrg1␤-induced Mtorc2-mediated Akt Phosphorylation At Sermentioning

confidence: 92%

Neuregulin-1β promotes glucose uptake via PI3K/Akt in neonatal rat cardiomyocytes

Pentassuglia

Heim

Lebboukh

et al. 2016

American Journal of Physiology-Endocrinology and Metabolism

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“…A diverse set of 1,5-triazole products can be found in these reports which cover a wide range of targets and target classes including various enzyme inhibitors, [203][204][205][206][207][208][209][210][211][212][213] kinases, [214][215][216][217] proteases, 110,112 antivirals 218 (see also chapter 5.3) G-protein coupled receptors (GPCRs), 219 ion channels, [220][221][222] heat shock proteins, 95 and tRNA ligands. 223 1,5-Triazole derivatives have shown activity against numerous cancer cell lines, 205,215,[224][225][226][227] and against the parasites Trypanosoma cruzi 70,228 and Plasmodium falciparum.…”

Section: Target-oriented Medicinal Chemistrymentioning

confidence: 99%

Ruthenium-Catalyzed Azide Alkyne Cycloaddition Reaction: Scope, Mechanism, and Applications

et al. 2016

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The ruthenium-catalyzed azide alkyne cycloaddition (RuAAC) affords 1,5-disubstituted 1,2,3-triazoles in one step and complements the more established copper-catalyzed reaction providing the 1,4-isomer. The RuAAC reaction has quickly found its way into the organic chemistry toolbox and found applications in many different areas, such as medicinal chemistry, polymer synthesis, organocatalysis, supramolecular chemistry and the construction of 2 electronic devices. This review discusses the mechanism, scope and applications of the RuAAC reaction, covering the literature during the last 10 years. CONTENTS

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“…Several changed upon PP2, but not bosutinib or imatinib treatment, and, based on previous studies, these changes would not be expected to facilitate healing (Brandonisio et al, 2002;LimaJunior et al, 2013;Muller et al, 2003;Oghumu et al, 2010;Ritter and Korner, 2002;Santiago et al, 2004). Of note, PP2 inhibits multiple targets, not just SFKs (>50 targets were seen in Brandvold et al, 2012), and these off-target effects could contribute to its chemokine and cytokine profile. More studies of chemokine secretion after host manipulations like kinase inhibition might be beneficial for unraveling the pathogenesis of leishmaniasis.…”

Section: **P=00023 (Two-tailed T-test) (E)mentioning

confidence: 99%

The Src kinases Hck, Fgr, and Lyn activate Abl2/Arg to facilitate IgG-mediated phagocytosis andLeishmaniainfection

Wetzel

Rhodes

et al. 2016

Journal of Cell Science

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Leishmaniasis is a devastating disease that disfigures or kills nearly two million people each year. Establishment and persistence of infection by the obligate intracellular parasite Leishmania requires repeated uptake by macrophages and other phagocytes. Therefore, preventing uptake could be a novel therapeutic strategy for leishmaniasis. Amastigotes, the life cycle stage found in the human host, bind Fc receptors and enter macrophages primarily through immunoglobulin-mediated phagocytosis. However, the host machinery that mediates amastigote uptake is poorly understood. We have previously shown that the Arg (also known as Abl2) nonreceptor tyrosine kinase facilitates L. amazonensis amastigote uptake by macrophages. Using small-molecule inhibitors and primary macrophages lacking specific Src family kinases, we now demonstrate that the Hck, Fgr and Lyn kinases are also necessary for amastigote uptake by macrophages. Src-mediated Arg activation is required for efficient uptake. Interestingly, the dual Arg and Src kinase inhibitor bosutinib, which is approved to treat cancer, not only decreases amastigote uptake, but also significantly reduces disease severity and parasite burden in Leishmania-infected mice. Our results suggest that leishmaniasis could potentially be treated with host-cellactive agents such as kinase inhibitors.

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Development of a Highly Selective c-Src Kinase Inhibitor

Cited by 112 publications

References 35 publications

Neuregulin-1β promotes glucose uptake via PI3K/Akt in neonatal rat cardiomyocytes

Neuregulin-1β promotes glucose uptake via PI3K/Akt in neonatal rat cardiomyocytes

Ruthenium-Catalyzed Azide Alkyne Cycloaddition Reaction: Scope, Mechanism, and Applications

The Src kinases Hck, Fgr, and Lyn activate Abl2/Arg to facilitate IgG-mediated phagocytosis andLeishmaniainfection

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