Chemicals

PIK-93 is the first reported PI4-kinase inhibitor which is able to inhibit PI4KIIIβ at low-nanomolar range (IC50=19 nM). In addition this compound is a potent inhibitor of PI3Kγ in vitro (IC50=16 nM). This compound inhibits p110α p110β p110δ with IC50's of 0.039 0.59 0.12 µM respectively. PIK-93 hydrogen bonds to the backbone amide and carbonyl of Val882 and between its sulphonamide and Asp964. PI4KIIIβ is essential for replication of numerous viruses P. falciparum. Inhibition of plasmodial PI4KIIIβ has been proposed as an anti-malaria treatment.References Powered by Bioz See more details on BiozJ.E. Burke et al. "Structures of PI4KIIIb complexes show simultaneous recruitment of Rab11 and its effectors" Science 344 1035 (2014); DOI: 10.1126/science.1253397

ZSTK474 is a potent inhibitor of all four isoforms of class I PI 3-kinase (α 6.7 nM β 10.4 nM γ 11.7 nM δ 1.8 nM). It binds to the ATP-binding pocket and is more active and less toxic than LY294002. ZSTK474 shows anti-tumor activity against human xenografts (A549 PC-3 WiDr) in mice by arresting cell growth. In addition it was able to inhibit osteoclast formation and collagen-induced arthritis in a mouse model.

SH2-Domain containing inositol 5-phosphatases (SHIP1 & SHIP2) dephosphorylate the 5-position of PI(3 4 5)P3 generating PI(3 4)P2. SHIP2 is ubiquitously expressed while SHIP1 is only found in hematopoietic lineage cells. 3AC is a selective inhibitor of SHIP1 (EC50 = 10 μM) and shows no inhibition of the other isoform SHIP2 at concentrations up to 1 mM. 3AC promotes apoptosis of SHIP1-expressing leukemia cells (KG-1) and multiple myeloma cells (OPM) suggesting SHIP1 inhibition is a potential drug target for blood cancers. Mice treated with 3AC show increased numbers of MIR cells in the spleen and lymph nodes and increased numbers of granulocytes. Powered by Bioz See more details on Bioz

AS1949490 is a potent selective SHIP2 inhibitor with IC50 of 0.62 uM for human which shows less effect on SHIP1 or no effects on some other types of intracellular phosphatases (such as PTEN synaptojanin and myotubularin). This compound also activates intracellular insulin signaling pathways in the liver and displays gluconeogensis regulation and antidiabetic effects.References Powered by Bioz See more details on BiozA. Suwa T. Yamanoto et al. "Discovery and functional characterization of a novel small molecule inhibitor of the intracellular phosphatase SHIP2" British Journal of Pharmacology 2009 158 879-88.

AS1938909 is a potent SHIP2 inhibitor (Ki = 0.44uM). This compound shows signficant selectivity over some related phosphatases (IC50 = 0.18uM 21uM >50uM for mSHIP2 hSHIP2 hPTEN respectively). It also enhances Akt phosphorylation and increases glucose consumption and uptake in L6 myotubes.ReferencesA Suwa T Yamanoto et al. "Glucose metabolism activation by SHIP2 inhibitors via up-regulation of GLUT1 gene in L6 myotubes" Eur J Pharmaco 2010 642 177

SH2-Domain containing inositol 5-phosphatases (SHIP1 & SHIP2) dephosphorylate the 5-position of PI(3 4 5)P3 generating PI(3 4)P2. PI(3 4)P2 activates Protein Kinase B (PKB/Akt) and promotes cell survival. SHIP2 expression and activity is increased in colorectal cancer suggesting an oncogenic role. Treatment of colorectal cancer cells with K149 (2uM) decreases PKB/Akt signaling and sensitizes the cells to 5-fluorouracil regardless of whether the cell lines have a PI3KCA mutation.References1) E. Hoekstra A.H. Das et al. “Lipid phosphatase SHIP2 functions as oncogene in colorectal cancer by regulating PKB activation” Oncotarget 2016; 7:73525-73540. DOI: 10.18632/oncotarget.12321

SF1670 is an inhibitor of PTEN (IC50 = 2 μM). PTEN (Phosphatase and Tensin Homolog deleted on Chromosome 10) is a 3’ phosphoinositide phosphatase that converts PI(3 4 5)P3 to PI(4 5)P2 thus opposing PKB/Akt activation by PI 3-K. Pretreatment of neutrophils with SF1670 leads to enhanced fMLP-1 induced PI(3 4 5)P3 signaling effects such as Akt phosphorylation NADPH oxidase-mediated superoxide formation cell polarization chemotactic migration and phagocytosis. SF1670 also inhibits CD45 (IC50 = 200 nM).Publications Powered by Bioz See more details on Bioz1) Cojohari O. et al. (2016). "Human cytomegalovirus induces an atypical activation of Akt to stimulate the survival of short-lived monocytes." J Virol 90(14): 6443-6452.2) Yousefi B. et al. (2017). "Balaglitazone reverses P-glycoprotein-mediated multidrug resistance via upregulation of PTEN in a PPARγ-dependent manner in leukemia cells." Tumor Biology 39(10): 1010428317716501.3) Alsina-Sanchís E. et al. (2018). "ALK1 (Activ

The vanadium complex VO-OHpic is a potent reversible allosteric inhibitor of phosphatase and tensin homologue deleted on chromosome 10 (PTEN) which hydrolyzes the 3-phosphate from phosphatidylinositol 3 4 5-trisphosphate (PIP3). PIP3 formed from PI(4 5)P2 though phosphorylation by PI 3-kinase activates numerous signaling pathways resulting in cell proliferation growth survival glucose transport and protein synthesis. VO-OHpic is reported to be selective for PTEN (IC50~35 nM) compared with other cysteine-based phosphatases (PTPβ SAC MTM & SopB IC50>4 μM). Treatment of insulin-stimulated NIH 3T3 and L1 fibroblasts caused an increase in Akt-phosphorylation indicating inhibition of PTEN in vivo.Publications Powered by Bioz See more details on Bioz

PS48 activates phosphoinositide-dependent protein kinase 1 (PDK1) by binding exclusively to PIF-binding pocket rather than the ATP binding site.References1) A. Stroba et al. “3 5-Diphenylpent-2-enoic Acids as Allosteric Activators of the Protein Kinase PDK1: Structure-Activity Relationships and Thermodynamic Characterization of Binding as Paradigms for PIF-Binding Pocket-Targeting Compounds” J. Med. Chem 2009 52 (15) 4683-46932) L.D. Spate et al. “PS48 can replace bovine serum albumin in pig embryo culture medium and improve in vitro embryo development by phosphorylating AKT” Molecular Reproduction & Development 2015 DOI: 10.1002/mrd.22474.