active compound concentration  (BASF)

Journal: Nature Reviews. Drug Discovery

Article Title: Targeting phospholipase D in cancer, infection and neurodegenerative disorders

doi: 10.1038/nrd.2016.252

Figure Lengend Snippet: a | Representative early indirect and direct inhibitors of phospholipase D (PLD). b | Second-generation PLD inhibitors that are based on halopemide (providing the first isoenzyme-selective PLD1 inhibitors). IC 50 , concentration that inhibits PLD activity by 50%; FIPI, 5-fluoro-2 indolyl des-chlorohalopemide.

Article Snippet: After decades of 'false starts', a brief report was published in 2007 in which a group at Novartis described halopemide ( , compound 8; concentration that inhibits PLD2 activity by 50% (IC 50 ) = 1.5 μM) and a set of 14 analogues as PLD2 inhibitors.

Techniques: Concentration Assay, Activity Assay

Journal: Nature Reviews. Drug Discovery

Article Title: Targeting phospholipase D in cancer, infection and neurodegenerative disorders

doi: 10.1038/nrd.2016.252

Figure Lengend Snippet: The phospholipase D 1 (PLD1) IC 50 values (concentration that inhibits PLD activity by 50%) were determined in cellular PLD1 assay with Calu-1 cells. The PLD2 IC 50 values were determined in a cellular assay with HEK293-GFP PLD2 cells. Each IC 50 was determined in triplicate measurements. X denotes H or halogen, and R 1 denotes the aryl- or cyclopropylaryl moieties (as listed in the table).

Article Snippet: After decades of 'false starts', a brief report was published in 2007 in which a group at Novartis described halopemide ( , compound 8; concentration that inhibits PLD2 activity by 50% (IC 50 ) = 1.5 μM) and a set of 14 analogues as PLD2 inhibitors.

Techniques: Concentration Assay, Activity Assay

Journal: Nature Reviews. Drug Discovery

Article Title: Targeting phospholipase D in cancer, infection and neurodegenerative disorders

doi: 10.1038/nrd.2016.252

Figure Lengend Snippet: VU0364739 (also known as JWJ; compound 12) emerged as an important phospholipase D2 (PLD2)-selective compound. IC 50 , concentration that inhibits PLD activity by 50%.

Article Snippet: After decades of 'false starts', a brief report was published in 2007 in which a group at Novartis described halopemide ( , compound 8; concentration that inhibits PLD2 activity by 50% (IC 50 ) = 1.5 μM) and a set of 14 analogues as PLD2 inhibitors.

Techniques: Concentration Assay, Activity Assay

Journal: Nature Reviews. Drug Discovery

Article Title: Targeting phospholipase D in cancer, infection and neurodegenerative disorders

doi: 10.1038/nrd.2016.252

Figure Lengend Snippet: 17–20 selective oestrogen receptor modulator (SERM) chemotypes have inhibitory activity against mammalian phospholipase D1 (PLD1), PLD2 and Pseudomonas aeruginosa PLD (PldA). IC 50 , concentration that inhibits PLD activity by 50%.

Article Snippet: After decades of 'false starts', a brief report was published in 2007 in which a group at Novartis described halopemide ( , compound 8; concentration that inhibits PLD2 activity by 50% (IC 50 ) = 1.5 μM) and a set of 14 analogues as PLD2 inhibitors.

Techniques: Activity Assay, Concentration Assay

Journal: Nature Reviews. Drug Discovery

Article Title: Targeting phospholipase D in cancer, infection and neurodegenerative disorders

doi: 10.1038/nrd.2016.252

Figure Lengend Snippet: The phospholipase D2 (PLD2) signalling axis is involved in both the entry and egress of influenza virus, as well as the process of autophagy, which can have antiviral function. PLD activity facilitates viral entry, whereas PLD inhibition delays the kinetics of viral endocytosis , thus widening the window of time in which the host cell can effectively prevent virus replication by producing antiviral effector molecules, such as interferon-induced transmembrane protein 3 (IFITM3) and MxA. Similarly, viral egress appears to be impaired by PLD inhibition . The regulation of AKT activity by PLD2 has also been shown to activate the autophagy pathway, which can limit virus production. PLD-generated phosphatidic acid (PtdOH) recruits AKT to cellular membranes, and AKT subsequently phosphorylates beclin 1 at serine 295. This leads to dissociation of the beclin 1–rubicon complex, a process that promotes autophagy. PLD inhibitors reduce PtdOH concentrations, reduce AKT-mediated phosphorylation of beclin 1 and stabilize the beclin 1–rubicon complex to stall autophagy. The changes depicted in membrane lipid composition are based on previous work that investigated the contributions of PtdOH to membrane curvature , .

Article Snippet: After decades of 'false starts', a brief report was published in 2007 in which a group at Novartis described halopemide ( , compound 8; concentration that inhibits PLD2 activity by 50% (IC 50 ) = 1.5 μM) and a set of 14 analogues as PLD2 inhibitors.

Techniques: Activity Assay, Inhibition, Generated

Journal: Nature Reviews. Drug Discovery

Article Title: Targeting phospholipase D in cancer, infection and neurodegenerative disorders

doi: 10.1038/nrd.2016.252

Figure Lengend Snippet: Left panel: phospholipase D2 (PLD2)-generated phosphatidic acid (PtdOH) recruits and binds to AKT and subsequently promotes autophagy via beclin 1, as detailed in . During the process of autophagy, autophagosomes fuse with endosomes and lysosomes, which leads to their maturation into autolysosomes. These display the autophagy markers LC3 (light chain 3, also known as MAP1LC3) and p62 (also known as sequestosome 1). This process results in acidification and allows the autolysosome to digest captured cellular material such as viruses. The respective details of PLD1 and PLD2 activation are discussed elsewhere . Right panel: this shows a PLD1 pathway that affects pyrimidine biosynthesis and intracellular deoxyribonucleotide triphosphate (dNTP) levels via the enzyme CAD (which contains carbamoyl aspartate synthase, aspartate transcarbamylase and dihydro-orotase domains). PLD1 allosterically modulates the activity of mechanistic target of rapamycin (mTOR), which leads to the phosphorylation of CAD and enhances its catalytic activity. The subsequent production of pyrimidine nucleotides via the activation of CAD is independent of AKT. PLD1 inhibition, in turn, can lead to reductions in dNTP production.

Article Snippet: After decades of 'false starts', a brief report was published in 2007 in which a group at Novartis described halopemide ( , compound 8; concentration that inhibits PLD2 activity by 50% (IC 50 ) = 1.5 μM) and a set of 14 analogues as PLD2 inhibitors.

Techniques: Generated, Activation Assay, Activity Assay, Inhibition