Virtual Screening Approach for the Identification of New Rac1 Inhibitors

Ferri, Nicola; Corsini, Alberto; Bottino, Paolo; Clerici, Francesca; Contini, Alessandro

doi:10.1021/jm8015987

Cited by 95 publications

(112 citation statements)

References 17 publications

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“…Therefore, the unexpected antagonistic effect of NSC23766 at mAChRs in the concentration range required to substantially suppress Tiam1-and Trio-mediated Rac1 activation will clearly limit its potential as novel therapeutic agent. Our data also imply a need for consequent testing of newly found "Rac1 inhibitors" (Ferri et al, 2009;Montalvo-Ortiz et al, 2012) for mAChR antagonistic properties before pursuing them further in drug development.…”

Section: Discussionmentioning

confidence: 91%

NSC23766, a Widely Used Inhibitor of Rac1 Activation, Additionally Acts as a Competitive Antagonist at Muscarinic Acetylcholine Receptors

Lévay

Krobert

Wittig

et al. 2013

J Pharmacol Exp Ther

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Small molecules interfering with Rac1 activation are considered as potential drugs and are already studied in animal models. A widely used inhibitor without reported attenuation of RhoA activity is NSC23766 [(. We found that NSC23766 inhibits the M 2 muscarinic acetylcholine receptor (M 2 mAChR)-induced Rac1 activation in neonatal rat cardiac myocytes. Surprisingly, NSC27366 concomitantly suppressed the carbachol-induced RhoA activation and a M 2 mAChR-induced inotropic response in isolated neonatal rat hearts requiring the activation of Rhodependent kinases. We therefore aimed to identify the mechanisms by which NSC23766 interferes with the differentially mediated, M 2 mAChR-induced responses. Interestingly, NSC23766 caused a rightward shift of the carbachol concentration response curve for the positive inotropic response without modifying carbachol efficacy. To analyze the specificity of NSC23766, we compared the carbachol and the similarly G i bg-mediated, adenosine-induced activation of G i protein-regulated potassium channel (GIRK) channels in human atrial myocytes. Application of NSC23766 blocked the carbachol-induced K 1 current but had no effect on the adenosine-induced GIRK current. Similarly, an adenosine A 1 receptor-induced positive inotropic response in neonatal rat hearts was not attenuated by NSC23766. To investigate its specificity toward the different mAChR types, we studied the carbachol-induced elevation of intracellular Ca 21 concentrations in human embryonic kidney 293 (HEK-293) cells expressing M 1 , M 2 , or M 3 mAChRs. NSC23766 caused a concentration-dependent rightward shift of the carbachol concentration response curves at all mAChRs. Thus, NSC23766 is not only an inhibitor of Rac1 activation, but it is within the same concentration range a competitive antagonist at mAChRs. Molecular docking analysis at M 2 and M 3 mAChR crystal structures confirmed this interpretation.

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Section: Discussionmentioning

confidence: 91%

NSC23766, a Widely Used Inhibitor of Rac1 Activation, Additionally Acts as a Competitive Antagonist at Muscarinic Acetylcholine Receptors

Lévay

Krobert

Wittig

et al. 2013

J Pharmacol Exp Ther

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“…The intracellular amount of Rac1-GTP and RhoA-GTP were determined by using the G-LISA assay as previously described (Cytoskeleton, Inc Denver, CO, USA) [23][24][25] . 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 11…”

Section: G-lisa Assay For Rac1 and Rhoamentioning

confidence: 99%

PCSK9 knock-out mice are protected from neointimal formation in response to perivascular carotid collar placement

et al. 2016

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Proprotein convertase subtilisin kexin type 9 (PCSK9) is a keyregulator of hepatic low-density lipoprotein-receptor (LDLR). PCSK9 is expressed in cultured smooth muscle cells (SMCs) and co-localizes with SMCs in human carotid atherosclerotic plaques. The present study aimed at comparing the neointimal lesions induced by periadventitial carotid placement of a non-occlusive collar in PCSK9 knock-out (PCSK9-/-) and wild type (WT) littermate (PCSK9+/+) mice. Collared carotids of the PCSK9-/-mice showed less intimal thickening compared to WT mice (p<0.05), a decreased intimal media ratio (p<0.02) and tendency to higher lumen area. When compared with PCSK9-/-, carotid lesions of WT mice had a higher content of SMCs (p<0.05) and collagen (p<0.05). No difference in macrophage content was detected between the two groups. SMCs freshly isolated from PCSK9-/-, when compared to PCSK9+/+ cells, showed higher levels of the contractile markers α-smooth muscle actin (α-SMA; 2.24±0.36 fold; p<0.01) and myosin heavy chain II (MHC-II; 8.65±1.55 fold; p<0.01), and decreased levels of synthetic markers caldesmon (-54±14%; p<0.01). PCSK9-/-cells also showed in response to platelet-derived growth factor-BB (PDGF-BB) a slower proliferation rate, and impaired migratory capacity and G1/S progression of the cell cycle. The reconstitution of PCSK9 expression, by retroviral infection of PCSK9-/-SMCs, led to a downregulation of α-SMA (-56±2%; p<0.01) and significant induction of caldesmon (1.46±0.3 fold; p<0.05). Proliferation rate of SMCs PCSK9-/-was significantly lower compared to PCSK9 reconstituted cells. Taken together, the present results suggest that by sustaining SMC synthetic phenotype, proliferation and migration PCSK9 may play a pro-atherogenic role in the arterial wall. HighlightsIn response to perivascular manipulation, the neointimal formation is reduced in PCSK9 -/-mice PCSK9 directly regulates smooth muscle cell differentiation, proliferation and migrationThe reconstitution of PCSK9 expression in SMCs PCSK9 -/-determines a switch towards a synthetic phenotype and rescue the impaired proliferation and migration capacities of SMCs PCSK9 -/-SMCs PCSK9 -/-respond less efficiently to the proliferative and chemotactic action of PDGF-BB 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 2 AbstractProprotein convertase subtilisin kexin type 9 (PCSK9) is a key-regulator of hepatic low-density lipoprotein-receptor (LDLR). PCSK9 is expressed in cultured smooth muscle cells (SMCs) and colocalizes with SMCs in human carotid atherosclerotic plaques. The present study aimed at comparing the neointimal lesions induced by periadventitial carotid placement of a non-occlusive collar in PCSK9 knock-out (PCSK9 -/-) and wild type (WT) littermate (PCSK9 +/+ ) mice. Collared carotids of the PCSK9 -/-mice showed less intimal thickening compared...

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“…2 In particular, our group is currently interested in synthetic methodologies to achieve novel sulfonamide derivatives which have been found useful as potential inhibitors of protein Rac1. 3 For those reasons, in this paper we describe a facile and versatile synthetic method to obtain azacycloalkene-monosulfonyl-diamines from accessible starting materials.…”

Section: Introductionmentioning

confidence: 99%

Click-chemistry approach to azacycloalkene monosulfonyl diamines: synthesis and computational analysis of the reaction mechanism

Contini

Erba

2012

RSC Adv.

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Click-chemistry approach to azacycloalkene monosulfonyl diamines: synthesis and computational analysis of the reaction mechanism{{ Alessandro Contini* and Emanuela Erba Received 27th July 2012, Accepted 7th September 2012 DOI: 10.1039/c2ra21592fThe cycloaddition reaction of the morpholino enamines of N-methylpiperidone and N-methyl tropinone with sulfonylazides was exploited, leading to a click-chemistry approach to uncommon azacycloalkene monosulfonyl diamines in good yields. A computational model for the key step decomposition of the triazoline intermediate was then realized by DFT calculations. The model explains the observed reaction outcome and leads to a new interpretation of the decomposition mechanism for 5-amino-1,2,3-triazolines. IntroductionVicinal diamines frequently appear as structural units in organic molecules of biological and medicinal interest, as well as in auxiliary groups or ligands for catalytic processes.1 Moreover it was demonstrated that monotosylated diamine complexes of Ru(II) form highly enantioselective catalysts for ketone reductions. 2 In particular, our group is currently interested in synthetic methodologies to achieve novel sulfonamide derivatives which have been found useful as potential inhibitors of protein Rac1. 3For those reasons, in this paper we describe a facile and versatile synthetic method to obtain azacycloalkene-monosulfonyl-diamines from accessible starting materials.Our group studied for a long time cycloaddition reactions and the subsequent rearrangement of the cycloadducts of aryl and sulfonyl azides with enamines of various aldehydes and linear or cyclic ketones. 4 In particular, when sulfonyl azides were used, the primary unstable dihydrotriazole cycloadduct underwent a spontaneous transformation and two main products were obtained: 2-alkyl-sulfonylamidine 1 by nitrogen loss and C-5 substituent transposition and the sulfonylformamidine 2 by alkyl diazomethane loss (Scheme 1). The obtained amidines were extensively used as syntones in heterocycle synthesis. 5 Aiming to obtain new synthetically useful starting materials, a number of carbonylic compounds have been used. It is known that the nature of the starting carbonyl reactant appears to rule the outcome of the reaction, and cyclic ketones containing a nitrogen atom showed an unexpected behaviour. 6 Consequently, one aim of this work was to thoroughly investigate the behaviour of alkylpiperidones and tropinones as the carbonylic reactant. Moreover, due to the peculiar regiochemical results herein obtained, an in-depth computational study of the reaction mechanism was performed. The results were in perfect agreement with the experiments and provided the evidence for a new interpretation of the mechanism of 5-amino-1,2,3-triazoline decomposition and rearrangement. Results and discussion ChemistryThe reaction between morpholino enamine of 1-methyl-4-piperidone 3 and tosyl azide 4a was initially investigated. By performing the reaction at room temperature in methylene dichloride as the solvent, we observed a ...

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Virtual Screening Approach for the Identification of New Rac1 Inhibitors

Cited by 95 publications

References 17 publications

NSC23766, a Widely Used Inhibitor of Rac1 Activation, Additionally Acts as a Competitive Antagonist at Muscarinic Acetylcholine Receptors

NSC23766, a Widely Used Inhibitor of Rac1 Activation, Additionally Acts as a Competitive Antagonist at Muscarinic Acetylcholine Receptors

PCSK9 knock-out mice are protected from neointimal formation in response to perivascular carotid collar placement

Click-chemistry approach to azacycloalkene monosulfonyl diamines: synthesis and computational analysis of the reaction mechanism

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