Discovery of AZD2716: A Novel Secreted Phospholipase A<sub>2</sub> (sPLA<sub>2</sub>) Inhibitor for the Treatment of Coronary Artery Disease

Giordanetto, Fabrizio; Pettersen, Daniel; Starke, Ingemar; Nordberg, Peter; Dahlström, Mikael; Knerr, Laurent; Selmi, Nidhal; Rosengren, Birgitta; Larsson, Lars-Olof; Sandmark, J.; Castaldo, Marie; Dekker, Niek; Karlsson, Ulla; Hurt-Camejo, Eva

doi:10.1021/acsmedchemlett.6b00188

Cited by 37 publications

(32 citation statements)

References 25 publications

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“…To investigate the binding mode of the synthesised inhibitors to different enzyme targets, molecular modelling techniques were deployed using the co-crystal structure of hG-X sPLA2 with the hit compound 1 reported by Giordanetto et al. 38 . In this co-crystal structure, the 4-benzylphenyl moiety of the inhibitor occupies a hydrophobic pocket, while the amide group coordinates with the catalytic site calcium.…”

Section: Resultsmentioning

confidence: 99%

“…The hydrazine nitrogen forms a critical coordination bond with the calcium ion present as a cofactor for the enzyme, similar to that of the amide moiety of the co-crystallised inhibitor. This interaction plays a central role in the inhibition of PLA2 activity 38 . The 3-methoxyphenyl moiety of 3f occupies the same hydrophobic pocket occupied by the 4-benzylphenyl moiety of the co-crystallised inhibitor.…”

Section: Resultsmentioning

confidence: 99%

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New quinoxalinone inhibitors targeting secreted phospholipase A2 and α-glucosidase

Alasmary

Alnahdi

Bacha

et al. 2017

Journal of Enzyme Inhibition and Medicinal Chemistry

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Elevated blood glucose and increased activities of secreted phospholipase A2 (sPLA2) are strongly linked to coronary heart disease. In this report, our goal was to develop small heterocyclic compound that inhibit sPLA2. The title compounds were also tested against α-glucosidase and α-amylase. This array of enzymes was selected due to their implication in blood glucose regulation and diabetic cardiovascular complications. Therefore, two distinct series of quinoxalinone derivatives were synthesised; 3-[N′-(substituted-benzylidene)-hydrazino]-1H-quinoxalin-2-ones 3a–f and 1-(substituted-phenyl)-5H-[1,2,4]triazolo[4,3-a]quinoxalin-4-ones 4a–f. Four compounds showed promising enzyme inhibitory effect, compounds 3f and 4b–d potently inhibited the catalytic activities of all of the studied proinflammatory sPLA2. Compound 3e inhibited α-glucosidase (IC50 = 9.99 ± 0.18 µM); which is comparable to quercetin (IC50 = 9.93 ± 0.66 µM), a known inhibitor of this enzyme. Unfortunately, all compounds showed weak activity against α-amylase (IC50 > 200 µM). Structure-based molecular modelling tools were utilised to rationalise the SAR compared to co-crystal structures with sPLA2-GX as well as α-glucosidase. This report introduces novel compounds with dual activities on biochemically unrelated enzymes mutually involved in diabetes and its complications.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

New quinoxalinone inhibitors targeting secreted phospholipase A2 and α-glucosidase

Alasmary

Alnahdi

Bacha

et al. 2017

Journal of Enzyme Inhibition and Medicinal Chemistry

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“… 23 We identified saturated LPC (LPC18:0) as the main LPC species present in the advanced atherosclerotic lesions, confirming the previous findings that showed the presence and the enzymatic activity of secretory phospholipase A2 in human lesions. 24 LPC associated with plasma lipoproteins accumulating in lesions can be another source of local LPC species. 25 LPA has been reported by others to be significantly higher in coronary than in peripheral systemic arterial blood.…”

Section: Discussionmentioning

confidence: 99%

Integrated Human Evaluation of the Lysophosphatidic Acid Pathway as a Novel Therapeutic Target in Atherosclerosis

Aldi

Matic

Hamm³

et al. 2018

Molecular Therapy - Methods & Clinical Development

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Variants in the PLPP3 gene encoding for lipid phosphate phosphohydrolase 3 have been associated with susceptibility to atherosclerosis independently of classical risk factors. PLPP3 inactivates lysophosphatidic acid (LPA), a pro-inflammatory, pro-thrombotic product of phospholipase activity. Here we performed the first exploratory analysis of PLPP3, LPA, and LPA receptors (LPARs 1–6) in human atherosclerosis. PLPP3 transcript and protein were repressed when comparing plaques versus normal arteries and plaques from symptomatic versus asymptomatic patients, and they were negatively associated with risk of adverse cardiovascular events. PLPP3 localized to macrophages, smooth muscle, and endothelial cells (ECs) in plaques. LPAR 2, 5, and especially 6 showed increased expression in plaques, with LPAR6 localized in ECs and positively correlated to PLPP3. Utilizing in situ mass spectrometry imaging, LPA and its precursors were found in the plaque fibrous cap, co-localizing with PLPP3 and LPAR6. In vitro, PLPP3 silencing in ECs under LPA stimulation resulted in increased expression of adhesion molecules and cytokines. LPAR6 silencing inhibited LPA-induced cell activation, but not when PLPP3 was silenced simultaneously. Our results show that repression of PLPP3 plays a key role in atherosclerosis by promoting EC activation. Altogether, the PLPP3 pathway represents a suitable target for investigations into novel therapeutic approaches to ameliorate atherosclerosis.

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“…These mutants reflect the different clinical manifestations and pharmacological action of tyrosine kinase inhibitors. In order to explore the possibility of the identified phytocompounds for multi-targeted therapy of NSCLC, the docking calculations were carried out with other proven drug targets with the chain A of HER2, ALK and sPLA2-IIA (PDB Id: 3PP0, Resolution: 2.25 Å, PDB Id: 4Z55, Resolution: 1.55 Å and PDB Id: 5G3N, Resolution: 3.526 Å respectively) ( Aertgeerts et al, 2011 , Michellys et al, 2016 , Giordanetto et al, 2016 ). Since our interest is to study the binding of identified phytocompounds with the catalytic domain of EML4-ALK, we have utilized the structure of the catalytic domain of ALK for the docking studies, given that the experimental structure of fusion protein of EML4-ALK is not available yet and the catalytic domain is identical in both EML4-ALK and ALK.…”

Section: Methodsmentioning

confidence: 99%

Identification of novel bioactive molecules from garlic bulbs: A special effort to determine the anticancer potential against lung cancer with targeted drugs

Padmini¹,

Maheshwari²,

Saravanan³

et al. 2020

Saudi Journal of Biological Sciences

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Garlic ( Allium sativum L.), is a predominant spice, which is used as an herbal medicine and flavoring agent, since ancient times. It has a rich source of various secondary metabolites such as flavonoids, terpenoids and alkaloids, which have various pharmacological properties. Garlic is used in the treatment of various ailments such as cancer, diabetes and cardiovascular diseases. The present study aims to explore the plausible mechanisms of the selected phytocompounds as potential inhibitors against the known drug targets of non-small-cell lung cancer (NSCLC). The phytocompounds of garlic were identified by gas chromatography-mass spectrometry (GC–MS) technique. Subsequently, the identified phytocompounds were subjected to molecular docking to predict the binding with the drug targets, epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER2), echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK) and group IIa secretory phospholipase A2 (sPLA2-IIA). Molecular dynamics is used to predict the stability of the identified phytocompounds against NSCLC drug targets by refining the intermolecular interactions formed between them. Among the 12 phytocompounds of garlic, three compounds[1,4-dimethyl-7-(1-methylethyl)-2-azulenyl]phenylmethanone, 2,4-bis(1-phenylethyl)-phenol and 4,5–2 h-oxazole-5-one,4-[3,5-di-t-butyl-4-methoxyphenyl] methylene-2-phenyl were identified as potential inhibitors, which might be suitable for targeting the different clinical forms of EGFR and dual inhibition of the studied drug targets to combat NSCLC. The result of this study suggest that these identified phytocompounds from garlic would serve as promising leads for the development of lead molecules to design new multi-targeting drugs to address the different clinical forms of NSCLC.

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Discovery of AZD2716: A Novel Secreted Phospholipase A₂ (sPLA₂) Inhibitor for the Treatment of Coronary Artery Disease

Cited by 37 publications

References 25 publications

New quinoxalinone inhibitors targeting secreted phospholipase A2 and α-glucosidase

New quinoxalinone inhibitors targeting secreted phospholipase A2 and α-glucosidase

Integrated Human Evaluation of the Lysophosphatidic Acid Pathway as a Novel Therapeutic Target in Atherosclerosis

Identification of novel bioactive molecules from garlic bulbs: A special effort to determine the anticancer potential against lung cancer with targeted drugs

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Discovery of AZD2716: A Novel Secreted Phospholipase A2 (sPLA2) Inhibitor for the Treatment of Coronary Artery Disease

Cited by 37 publications

References 25 publications

New quinoxalinone inhibitors targeting secreted phospholipase A2 and α-glucosidase

New quinoxalinone inhibitors targeting secreted phospholipase A2 and α-glucosidase

Integrated Human Evaluation of the Lysophosphatidic Acid Pathway as a Novel Therapeutic Target in Atherosclerosis

Identification of novel bioactive molecules from garlic bulbs: A special effort to determine the anticancer potential against lung cancer with targeted drugs

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Discovery of AZD2716: A Novel Secreted Phospholipase A₂ (sPLA₂) Inhibitor for the Treatment of Coronary Artery Disease