3-Aryl-N-aminoylsulfonylphenyl-1H-pyrazole-5-carboxamides: a new class of selective Rac inhibitors

Ferri, Nicola; Bernini, Sergio Kevin; Corsini, Alberto; Clerici, Francesca; Erba, Emanuela; Stragliotto, Stefano; Contini, Alessandro

doi:10.1039/c2md20328f

Cited by 25 publications

(40 citation statements)

References 22 publications

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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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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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“…[45a, 77] Further virtual screens explored the SARs and the most promising analogue had an IC 50 value of 8.7 mm in cellbased assays. [78] Another campaign identified ZINC69391 (40), which blocked the Rac1-GEF interaction and Rac1 activity in cells,and was optimized to give 1A-116 (41). [79] 41 had an IC 50 value of 4 mm for the antiproliferation of F3II cancer cells,w as more potent in blocking GEF activation in vitro than 40,a nd caused a6 0% reduction in metastatic lung colonies in vivo.Adifferent approach used de novo design to yield an inhibitor that would have the same pharmacophoric features as 38 and other previous compounds but au nrelated scaffold.…”

Section: Direct Inhibition Of the Rho Gtpases (Methods A)mentioning

confidence: 99%

“…identified N ‐(sulfamoylaryl)arylamide ZINC08010136 ( 39 , Figure A) as a Rac1‐selective inhibitor that could interfere with GEF/GTPase complex formation and Rac1 activity in cells (IC 50 =12 μ m ), although it has high structural similarity to a known aggregator . Further virtual screens explored the SARs and the most promising analogue had an IC 50 value of 8.7 μ m in cell‐based assays . Another campaign identified ZINC69391 ( 40 ), which blocked the Rac1–GEF interaction and Rac1 activity in cells, and was optimized to give 1A‐116 ( 41 ) .…”

Section: Rho Gtpasesmentioning

confidence: 99%

Targeting the Small GTPase Superfamily through Their Regulatory Proteins

2020

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The Ras superfamily of small GTPases are guanine‐nucleotide‐dependent switches essential for numerous cellular processes. Mutations or dysregulation of these proteins are associated with many diseases, but unsuccessful attempts to target the small GTPases directly have resulted in them being classed as “undruggable”. The GTP‐dependent signaling of these proteins is controlled by their regulators; guanine nucleotide exchange factors (GEFs), GTPase activating proteins (GAPs), and in the Rho and Rab subfamilies, guanine nucleotide dissociation inhibitors (GDIs). This review covers the recent small molecule and biologics strategies to target the small GTPases through their regulators. It seeks to critically re‐evaluate recent chemical biology practice, such as the presence of PAINs motifs and the cell‐based readout using compounds that are weakly potent or of unknown specificity. It highlights the vast scope of potential approaches for targeting the small GTPases in the future through their regulatory proteins.

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“…identifizierten das N ‐(Sulfamoylaryl)arylamid ZINC08010136 ( 39 , Abbildung A) als einen Rac1‐selektiven Inhibitor, der die GEF/GTPase‐Komplexbildung und Rac1‐Aktivität in Zellen stören könnte (IC 50 12 μ m ), obwohl es deutliche strukturelle Ähnlichkeit mit einem bekannten Aggregator hat . Weitere virtuelle Screenings erforschten die SARs und das vielversprechendste Analogon hatte in zellbasierten Assays einen IC 50 von 8.7 μ m . Eine weitere Kampagne identifizierte ZINC69391 ( 40 ), das die Rac1‐GEF‐Interaktion und die Rac1‐Aktivität in Zellen blockiert.…”

Section: Rho‐gtpasenunclassified

Targeting der kleinen GTPasen über ihre regulatorischen Proteine

2020

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Die kleinen GTPasen der Ras‐Superfamilie sind Guaninnukleotid‐abhängige Schalter, die für eine Vielzahl zellulärer Prozesse essentiell sind. Mutationen oder Dysregulationen dieser Proteine stehen in Verbindung mit zahlreichen Erkrankungen. Erfolglose Versuche, die kleinen GTPasen direkt als Zielstruktur anzugreifen, führten zu ihrer Klassifizierung als pharmakologisch nicht adressierbar (“undruggable”). Der GTP‐abhängige Signalweg dieser Proteine wird durch ihre Regulatoren kontrolliert, sogenannte “guanine nucleotide exchange factors” (GEFs), “GTPase activating proteins” (GAPs) und in der Rho‐ und Rab‐Subfamilie “guanine nucleotide dissociation inhibitors” (GDIs). Dieser Aufsatz beinhaltet die neusten niedermolekularen und biologischen Strategien, um die kleinen GTPasen durch ihre Regulatoren als Zielstruktur anzugreifen. Wir geben eine kritische Re‐Evaluierung der jüngsten chemisch biologischen Vorgehensweisen, wie dem Vorhandensein von PAINs‐Motiven und zellbasierter Auslese mit Verbindungen, die schwach potent sind oder eine unbekannte Spezifität haben, uns diskutieren das breite Feld potentieller Ansätze, um die kleinen GTPasen zukünftig durch ihre regulatorischen Proteine anzugreifen.

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3-Aryl-N-aminoylsulfonylphenyl-1H-pyrazole-5-carboxamides: a new class of selective Rac inhibitors

Cited by 25 publications

References 22 publications

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

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

Targeting the Small GTPase Superfamily through Their Regulatory Proteins

Targeting der kleinen GTPasen über ihre regulatorischen Proteine

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