Discovery of 4-(dihydropyridinon-3-yl)amino-5-methylthieno[2,3-d]pyrimidine derivatives as potent Mnk inhibitors: synthesis, structure–activity relationship analysis and biological evaluation

Yu, Mingfeng; Li, Peng; Basnet, Sunita K. C.; Kumarasiri, Malika; Diab, Sarah; Teo, Theodosia; Albrecht, Hugo; Wang, Shudong

doi:10.1016/j.ejmech.2015.03.032

Cited by 31 publications

(25 citation statements)

References 33 publications

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“…Electrophysiologically, there are studies showing that histamine can induce and enhance spontaneous firing of neurons in the vestibular nucleus in rats, effects that are reduced by mepyramine and the H 2 receptor antagonist, cimetidine. However, mepyramine alone did not appear to have any effect to depolarize or hyperpolarize neurons, or to change the frequency of spontaneous firing (Yu et al, 2015). In another rat study, histamine reportedly induced firing of neurons in the NTS, which was blocked by the H 1 receptor antagonist, triprolidine.…”

Section: Discussionmentioning

confidence: 99%

Brain Activation by H1 Antihistamines Challenges Conventional View of Their Mechanism of Action in Motion Sickness: A Behavioral, c-Fos and Physiological Study in Suncus murinus (House Musk Shrew)

Dieser

et al. 2017

Front. Physiol.

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Motion sickness occurs under a variety of circumstances and is common in the general population. It is usually associated with changes in gastric motility, and hypothermia, which are argued to be surrogate markers for nausea; there are also reports that respiratory function is affected. As laboratory rodents are incapable of vomiting, Suncus murinus was used to model motion sickness and to investigate changes in gastric myoelectric activity (GMA) and temperature homeostasis using radiotelemetry, whilst also simultaneously investigating changes in respiratory function using whole body plethysmography. The anti-emetic potential of the highly selective histamine H1 receptor antagonists, mepyramine (brain penetrant), and cetirizine (non-brain penetrant), along with the muscarinic receptor antagonist, scopolamine, were investigated in the present study. On isolated ileal segments from Suncus murinus, both mepyramine and cetirizine non-competitively antagonized the contractile action of histamine with pKb values of 7.5 and 8.4, respectively; scopolamine competitively antagonized the contractile action of acetylcholine with pA2 of 9.5. In responding animals, motion (1 Hz, 4 cm horizontal displacement, 10 min) increased the percentage of the power of bradygastria, and decreased the percentage power of normogastria whilst also causing hypothermia. Animals also exhibited an increase in respiratory rate and a reduction in tidal volume. Mepyramine (50 mg/kg, i.p.) and scopolamine (10 mg/kg, i.p.), but not cetirizine (10 mg/kg, i.p.), significantly antagonized motion-induced emesis but did not reverse the motion-induced disruptions of GMA, or hypothermia, or effects on respiration. Burst analysis of plethysmographic-derived waveforms showed mepyramine also had increased the inter-retch+vomit frequency, and emetic episode duration. Immunohistochemistry demonstrated that motion alone did not induce c-fos expression in the brain. Paradoxically, mepyramine increased c-fos in brain areas regulating emesis control, and caused hypothermia; it also appeared to cause sedation and reduced the dominant frequency of slow waves. In conclusion, motion-induced emesis was associated with a disruption of GMA, respiration, and hypothermia. Mepyramine was a more efficacious anti-emetic than cetirizine, suggesting an important role of centrally-located H1 receptors. The ability of mepyramine to elevate c-fos provides a new perspective on how H1 receptors are involved in mechanisms of emesis control.

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Section: Discussionmentioning

confidence: 99%

Brain Activation by H1 Antihistamines Challenges Conventional View of Their Mechanism of Action in Motion Sickness: A Behavioral, c-Fos and Physiological Study in Suncus murinus (House Musk Shrew)

Dieser

et al. 2017

Front. Physiol.

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“…Until now, only a few small-molecule inhibitors have been described. CGP57380 is a Mnk inhibitor which exhibits cytotoxic effects against cancer cells at low micromolar concentration, yet was also shown to inhibit other kinases [10, 61]. CGP57380 blocks eIF4E phosphorylation on Ser209, but also was shown to decrease rpS6 phosphorylation in CML cell lines [62].…”

Section: Strategies For Targeting Eif4e In Amlmentioning

confidence: 99%

Dual targeting of eIF4E by blocking MNK and mTOR pathways in leukemia

2017

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Dysregulation of mRNA translation leads to aberrant activation of cellular pathways that promote expansion and survival of leukemic clones. A key element of the initiation translation complex is eIF4E (eukaryotic translation initiation factor 4E). The mitogen-activated protein kinase (MAPK) and mammalian target of rapamycin (mTOR) pathways play important roles in the regulation of eIF4E expression and downstream functional outcomes. Mitogen-activated protein kinase interacting protein kinases (Mnks) control translation by phosphorylation of eIF4E, whereas the mTOR kinase phosphorylates/de-activates the eIF4E inhibitor, 4E-BP1, to release translational repression. Both pathways are often abnormally activated in leukemia cells and promote cell survival events by controlling expression of oncogenic proteins. Targeting these pathways may provide approaches to avoid aberrant proliferation and neoplastic transformation.

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“…We previously showed that inhibition of Mnks caused cell typespecific cytoxicity (Diab et al, 2014b;Yu et al, 2015). Most pronounced cytotoxic effects have been observed in Fms-like tyrosine kinase 3 overexpressing leukemia cells (Altman et al, 2013;Lim et al, 2013;Diab et al, 2014b;Teo et al, 2015a).…”

Section: Discussionmentioning

confidence: 98%

“…These compounds were used as references for kinase assays. Compounds of series 1 (N-phenylthieno[2,3-d]pyrimidin-4-amines), series 2 (3,4-dimethyl-5-(2-(phenylamino)pyrimidin-4-yl)thiazol-2(3H)-ones), and series 3 (N-phenyl-1H-pyrazolo [3,4-d]pyrimidin-3-amine) were synthesized in our laboratory as reported previously (Diab et al, 2014b;Teo et al, 2015a,b;Yu et al, 2015) and were dissolved in dimethylsulfoxide at 10 mM concentration and stored at 220°C.…”

Section: Compoundsmentioning

confidence: 99%

“…Despite the fact that Mnks could potentially be effective targets for cancer therapy with better outcomes and fewer side effects, only limited advancement has been made in developing pharmacological inhibitors. For example, CGP57380 has been described as Mnk inhibitor and exhibited activity in cancer cells at micromolar concentrations (Diab et al, 2014b;Teo et al, 2015b;Yu et al, 2015), but it also inhibited several other kinases with similar potency (Bain et al, 2007). Another Mnk inhibitor, cercosporamide (Sussman et al, 2004), was recently shown to have antitumor activity in human tumor xenografts (Konicek et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

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Identification of a Highly Conserved Allosteric Binding Site on Mnk1 and Mnk2

et al. 2015

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Elevated levels of phosphorylated eukaryotic initiation factor 4E (eIF4E) have been implicated in many tumor types, and mitogen activated protein kinase-interacting kinases (Mnks) are the only known kinases that phosphorylate eIF4E at Ser209. The phosphorylation of eIF4E is essential for oncogenic transformation but is of no significance to normal growth and development. Pharmacological inhibition of Mnks therefore provides a nontoxic and effective strategy for cancer therapy. However, a lack of specific Mnk inhibitors has confounded pharmacological target validation and clinical development. Herein, we report the identification of a novel series of Mnk inhibitors and their binding modes. A systematic workflow has been established to distinguish between type III and type I/II inhibitors. A selection of 66 compounds was tested for Mnk1 and Mnk2 inhibition, and 9 out of 20 active compounds showed type III interaction with an allosteric site of the proteins. Most of the type III inhibitors exhibited dual Mnk1 and Mnk2 activities and demonstrated potent antiproliferative properties against the MV4-11 acute myeloid leukemia cell line. Interestingly, ATP-/ substrate-competitive inhibitors were found to be highly selective for Mnk2, with little or no activity for Mnk1. Our study suggests that Mnk1 and Mnk2 share a common structure of the allosteric inhibitory binding site but possess different structural features of the ATP catalytic domain. The findings will assist in the future design and development of Mnk targeted anticancer therapeutics.

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Discovery of 4-(dihydropyridinon-3-yl)amino-5-methylthieno[2,3-d]pyrimidine derivatives as potent Mnk inhibitors: synthesis, structure–activity relationship analysis and biological evaluation

Cited by 31 publications

References 33 publications

Brain Activation by H1 Antihistamines Challenges Conventional View of Their Mechanism of Action in Motion Sickness: A Behavioral, c-Fos and Physiological Study in Suncus murinus (House Musk Shrew)

Brain Activation by H1 Antihistamines Challenges Conventional View of Their Mechanism of Action in Motion Sickness: A Behavioral, c-Fos and Physiological Study in Suncus murinus (House Musk Shrew)

Dual targeting of eIF4E by blocking MNK and mTOR pathways in leukemia

Identification of a Highly Conserved Allosteric Binding Site on Mnk1 and Mnk2

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