Design and synthesis of isoform-selective phospholipase D (PLD) inhibitors. Part I: Impact of alternative halogenated privileged structures for PLD1 specificity

Lewis, Jana A.; Scott, Sarah; Lavieri, Robert R.; Buck, Jason R.; Selvy, Paige E.; Stoops, Sydney L.; Armstrong, Michelle D.; Brown, H. Alex; Lindsley, Craig W.

doi:10.1016/j.bmcl.2009.02.057

Cited by 100 publications

(95 citation statements)

References 20 publications

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“…The mammalian PLD1-specific inhibitor VU0359595 (Avanti product no. 857371) (42), the PLD2-specific inhibitor VU0285655-1 (Avanti product no. 857372) (39), and PA (Avanti product no.…”

Section: Methodsmentioning

confidence: 99%

Disruption of the Phospholipase D Gene Attenuates the Virulence of Aspergillus fumigatus

Gao

Han

et al. 2012

Infect Immun

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Aspergillus fumigatus is the most prevalent airborne fungal pathogen that induces serious infections in immunocompromised patients. Phospholipases are key enzymes in pathogenic fungi that cleave host phospholipids, resulting in membrane destabilization and host cell penetration. However, knowledge of the impact of phospholipases on A. fumigatus virulence is rather limited. In this study, disruption of the pld gene encoding phospholipase D (PLD), an important member of the phospholipase protein family in A. fumigatus, was confirmed to significantly decrease both intracellular and extracellular PLD activity of A. fumigatus. The pld gene disruption did not alter conidial morphological characteristics, germination, growth, and biofilm formation but significantly suppressed the internalization of A. fumigatus into A549 epithelial cells without affecting conidial adhesion to epithelial cells. Importantly, the suppressed internalization was fully rescued in the presence of 100 M phosphatidic acid, the PLD product. Indeed, complementation of pld restored the PLD activity and internalization capacity of A. fumigatus. Phagocytosis of A. fumigatus conidia by J774 macrophages was not affected by the absence of the pld gene. Pretreatment of conidia with 1-butanol and a specific PLD inhibitor decreased the internalization of A. fumigatus into A549 epithelial cells but had no effect on phagocytosis by J774 macrophages. Finally, loss of the pld gene attenuated the virulence of A. fumigatus in mice immunosuppressed with hydrocortisone acetate but not with cyclophosphamide. These data suggest that PLD of A. fumigatus regulates its internalization into lung epithelial cells and may represent an important virulence factor for A. fumigatus infection.

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“…The mammalian PLD1-specific inhibitor VU0359595 (Avanti product no. 857371) (42), the PLD2-specific inhibitor VU0285655-1 (Avanti product no. 857372) (39), and PA (Avanti product no.…”

Section: Methodsmentioning

confidence: 99%

Disruption of the Phospholipase D Gene Attenuates the Virulence of Aspergillus fumigatus

Gao

Han

et al. 2012

Infect Immun

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“…The benzimidazolinone-piperidine group is frequently seen in differently targeted active compounds other than pimozide, [18][19][20] representing an important privileged structure for biological activities. Therefore, in our investigation, we chose the benzimidazolinone-piperidine portion of pimozide as a steady point.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of activated STAT5 in Bcr/Abl expressing leukemia cells with new pimozide derivatives

Rondanin

Daniele

Romagnoli

et al. 2014

Bioorganic & Medicinal Chemistry Letters

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a b s t r a c tSTATs are transcription factors acting as intracellular signaling after stimulation with cytokines, growth factors and hormones. STAT5 is also constitutively active in many forms of cancers, including chronic myelogenous leukemia, acute lymphoblastic leukemia and Hodgkin's lymphoma. Recently, literature reported that the neuroleptic drug pimozide inhibits STAT5 phosphorylation inducing apoptosis in CML cells. We undertook an investigation from pimozide structure, obtaining simple derivatives with cytotoxic and STAT5-inhibitory activity, two of them markedly more potent than pimozide.Ó 2014 Elsevier Ltd. All rights reserved.Signal transducers and activators of transcription (STATs) are transcription factors that act as intracellular signaling after stimulation with cytokines, growth factors and hormones. STATs are activated into the cytosol by phosphorylation of specific tyrosine residues forming homo-or heterodimers that enter into the nucleus and bind to the specific DNA sequences in the promoter regions of various genes involved in cell survival, proliferation and differentiation. 1 STAT5 protein consists of a N-terminal domain that is involved in promoting STAT5 dimerization, a DNA binding domain that interacts with a conserved DNA binding sequence, an SH2 domain that drives the initial interaction of STAT5 protein with phosphorylated tyrosine residues in the cytoplasmic tails of cytokine receptors, and a C-terminal transactivation domain. 2 In order to be functional, STAT5 proteins must first be activated. This activation is carried out by kinases associated with transmembrane receptors. Firstly, ligands (cytokines, growth factors) binding to these transmembrane receptors on the outside of the cell activate JAK2 (Janus kinase 2) which in turn add a phosphate group to a specific tyrosine residue on the receptor; STAT5 then binds to these phosphorylated-tyrosines using their SH2 domain. The bound STAT5 is then phosphorylated by JAK2 and the phosphorylated STAT5 finally goes on to form either homodimers, STAT5-STAT5, or heterodimers, STAT5-STATX, with other STAT proteins. 3,4 The interest of STAT5 in oncology comes from the initial observations of its activation in many malignancies. Epigenetic changes, regulation by miRNA, altered proteolytic pathways, gene amplification and aberrant growth factor signaling contribute to activation of STAT5 proteins in human cancers; however, mutations in STAT5 genes have not been found, with the exception of myeloid leukemia, where the STAT5 C-terminal part fuses with RARa. In contrast, mutations in signaling pathways acting upstream of STAT5 proteins are frequent in many cancer types.Constitutively STAT5 activation was found in hematological malignancies such as acute lymphocytic leukemia (ALL), erythroleukemia, chronic myelogenous leukemia (CML) and in others myeloproliferative diseases. 5 Differently from normal cells in which STAT5 is activated by JAK2, in ALL and CML the products of the fusion proteins TEL/ JAK2 and BCR/ABL activate directly STAT5 proteins...

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“…Interestingly, incorporation of the (R)-methyl group led to a diminution in potency at both PLD1 and PLD2. Thus, a tool kit of PLD1-selective, PLD2-selective, and dual PLD1/2 inhibitors with good DMPK profiles that display either peripheral restriction or CNS exposure are now available to dissect the therapeutic potential and physiologic roles of direct and selective inhibition of the PLD isoforms both in vitro and in vivo (Lavieri et al, , 2010Lewis et al, 2009;Scott et al, 2009).…”

Section: Phospholipase D Small-molecule Inhibitorsmentioning

confidence: 99%

Phospholipase D Signaling Pathways and Phosphatidic Acid as Therapeutic Targets in Cancer

2014

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Design and synthesis of isoform-selective phospholipase D (PLD) inhibitors. Part I: Impact of alternative halogenated privileged structures for PLD1 specificity

Cited by 100 publications

References 20 publications

Disruption of the Phospholipase D Gene Attenuates the Virulence of Aspergillus fumigatus

Disruption of the Phospholipase D Gene Attenuates the Virulence of Aspergillus fumigatus

Inhibition of activated STAT5 in Bcr/Abl expressing leukemia cells with new pimozide derivatives

Phospholipase D Signaling Pathways and Phosphatidic Acid as Therapeutic Targets in Cancer

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