Inhibition of P-selectin specific cell adhesion by a low molecular weight, non-carbohydrate compound, KF38789

Ohta, Shuji; Inujima, Y.; Abe, Masayuki; Uosaki, Youichi; Sato, Seiji; Miki, Ichiro

doi:10.1007/pl00000232

Cited by 23 publications

(21 citation statements)

References 34 publications

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“…E, F). To further validate the role of P‐selectin, embryos were treated with KF38789, a selective inhibitor of P‐selectin‐mediated cell adhesion ; CD41:eGFP + cell counts showed that KF38789 also caused reduced CHT colonization, particularly in AM1241‐treated embryos (Fig. G, H).…”

Section: Resultsmentioning

confidence: 99%

Cannabinoid Receptor-2 Regulates Embryonic Hematopoietic Stem Cell Development via Prostaglandin E2 and P-Selectin Activity

et al. 2015

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Cannabinoids (CB) modulate adult hematopoietic stem and progenitor cell (HSPCs) function, however, impact on the production, expansion, or migration of embryonic HSCs is currently uncharacterized. Here, using chemical and genetic approaches targeting CB-signaling in zebrafish, we show that CB receptor (CNR) 2, but not CNR1, regulates embryonic HSC development. During HSC specification in the aorta-gonad-mesonephros (AGM) region, CNR2 stimulation by AM1241 increased runx1;cmyb+ HSPCs, through heightened proliferation, whereas CNR2 antagonism decreased HSPC number; FACS analysis and absolute HSC counts confirmed and quantified these effects. Epistatic investigations showed AM1241 significantly upregulated PGE2 synthesis in a Ptgs2-dependent manner to increase AGM HSCs. During the phases of HSC production and colonization of secondary niches, AM1241 accelerated migration to the caudal hematopoietic tissue (CHT), the site of embryonic HSC expansion, and the thymus; however these effects occurred independently of PGE2. Using a candidate approach for HSC migration and retention factors, P-selectin was identified as the functional target of CNR2 regulation. Epistatic analyses confirmed migration of HSCs into the CHT and thymus was dependent on CNR2-regulated P-selectin activity. Together, these data suggest CNR2-signaling optimizes the production, expansion, and migration of embryonic HSCs by modulating multiple downstream signaling pathways.

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Section: Resultsmentioning

confidence: 99%

Cannabinoid Receptor-2 Regulates Embryonic Hematopoietic Stem Cell Development via Prostaglandin E2 and P-Selectin Activity

et al. 2015

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“…B). Three well‐known tubulin disruptors (vincristine, vinblastine and colchicine), one tubulin stabilizer (Taxol) and KF 38789, which was originally identified as a selective inhibitor of P‐selectin‐mediated cell adhesion and recently identified as a tubulin disruptor , were classified into the same cluster. These results suggested that the calculated parameters and cluster analysis work well and reflect the features of cellular status.…”

Section: Resultsmentioning

confidence: 99%

Vacuolin‐1 inhibits autophagy by impairing lysosomal maturation via PIKfyve inhibition

et al. 2016

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Lysosomal protein degradation via autophagy strictly regulates cellular protein homoeostasis. Herein we performed high-content screening to identify compounds that inhibit autophagy pathways. We obtained 11 hit compounds and performed cluster analysis using cellular morphological information. Vacuolin-1, which induces the formation of giant vacuoles and is a target unknown compound, clustered with the known PIKfyve inhibitor YM201636. We further confirmed that vacuolin-1 is a potent PIKfyve inhibitor, and we finally concluded that PIKfyve inhibitors are novel chemical tools for regulating autophagy.

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“…Several studies have identified selectins as potential targets for the design of novel antiinflammatory agents, including selectin antagonists (19-22, 24, 34-42) and selectin-targeted immunoliposomes designed for local delivery of compounds to the endothelium (43)(44)(45)(46). Research has focused on identifying the structural features required for high selectin binding affinity, and based on these studies, some low molecular weight, noncarbohydrate, nonpeptide inhibitors of P-selectin have been identified (34)(35)(36)(37)40). Therapeutically viable P-selectin inhibitors have proven difficult to realize due to the weak binding of the monovalent ligands and extreme cost associated with the production of physiological ligand-based inhibitors such as sLe x or PSGL-1.…”

Section: Discussionmentioning

confidence: 99%

Discovery of a potent nanoparticle P‐selectin antagonist with anti‐inflammatory effects in allergic airway disease

et al. 2003

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The severity of allergic asthma is dependent, in part, on the intensity of peribronchial inflammation. P-selectin is known to play a role in the development of allergen-induced peribronchial inflammation and airway hyperreactivity. Selective inhibitors of P-selectin-mediated leukocyte endothelial-cell interactions may therefore attenuate the inflammatory processes associated with allergic airway disease. Novel P-selectin inhibitors were created using a polyvalent polymer nanoparticle capable of displaying multiple synthetic, low molecular weight ligands. By assembling a particle that presents an array of groups, which as monomers interact with only low affinity, we created a construct that binds extremely efficiently to P-selectin. The ligands acted as mimetics of the key binding elements responsible for the high-avidity adhesion of P-selectin to the physiologic ligand, PSGL-1. The inhibitors were initially evaluated using an in vitro shear assay system in which interactions between circulating cells and P-selectin-coated capillary tubes were measured. The nanoparticles were shown to preferentially bind to selectins expressed on activated endothelial cells. We subsequently demonstrated that nanoparticles displaying P-selectin blocking arrays were functionally active in vivo, significantly reducing allergen-induced airway hyperreactivity and peribronchial eosinophilic inflammation in a murine model of asthma.

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Inhibition of P-selectin specific cell adhesion by a low molecular weight, non-carbohydrate compound, KF38789

Abstract: A novel low molecular weight compound, KF38789, specifically inhibited P-selectin-dependent cell adhesion and the leukocyte recruitment in mouse peritonitis.

Cited by 23 publications

References 34 publications

Cannabinoid Receptor-2 Regulates Embryonic Hematopoietic Stem Cell Development via Prostaglandin E2 and P-Selectin Activity

Cannabinoid Receptor-2 Regulates Embryonic Hematopoietic Stem Cell Development via Prostaglandin E2 and P-Selectin Activity

Vacuolin‐1 inhibits autophagy by impairing lysosomal maturation via PIKfyve inhibition

Discovery of a potent nanoparticle P‐selectin antagonist with anti‐inflammatory effects in allergic airway disease

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