Chemicals & Small Molecules

5-(2 2-Difluoro-benzo[1 3]dioxol-5-ylmethylene)-thiazolidine-2 4-dione (AS604850) is an inhibitor of PI 3-Kγ with an IC50 = 250 nM. AS604850 is selective for the γ-isoform (IC50: PI 3-Kα = 4.5 μM PI 3-Kβ PI 3-Kδ > 20 μM) and shows no notable activity against a wide array of protein kinases at 1 μM.References Powered by Bioz See more details on Bioz1) M. Camps et al. "Blockade of PI3Kg suppresses joint inflammation and damage in mouse models of rheumatoid arthritis" Nature Medicine 2005 11 936-943.

PI-103 is a selective inhibitor for the α-isoform of PI 3-Kinase (IC50: PI 3-Kα = 8 nM PI 3-Kβ = 88 nM PI 3-Kδ = 48 nM PI 3-Kγ = 150 nM). It is also inhibits DNA-PK (IC50 = 2 nM) and mTOR1 and mTOR2 (IC50 = 20 & 83 nM). PI-103 shows little activity against a wide array of protein kinases at 10μM. PI-103 blocks glioma proliferation by blocking the PI 3-K/Akt pathway in vitro and in vivo.References Powered by Bioz See more details on Bioz1) Fan Q. et al. (2006) ."A dual PI3 kinase/mTOR inhibitor reveals emergent efficacy in glioma." Cancer Cell 9: 341-349.2) Smit M. A. T. R. Geiger et al. (2009). "A Twist-Snail axis critical for TrkB-induced epithelial-mesenchymal transition-like transformation anoikis resistance and metastasis." Mol Cell Biol 29(13): 3722-37.3) Gursel D. B. Y. S. Connell-Albert et al. (2011). "Control of proliferation in astrocytoma cells by the receptor tyrosine kinase/PI3K/AKT signaling axis and the use of PI-103 and TCN as potential anti-astro

3-(4-Morpholinothieno[3 2-d]pyrimidin-2-yl)phenol is a selective inhibitor for the α-isoform of PI 3-Kinase (IC50: PI 3-Kα = 2 nM PI 3-Kβ = 16 nM PI3-Kγ = 660 nM PI3KC2β = 220 nM)). It showed >1000-fold selectivity vs. protein kinases such as PKA KDR PKCa and E/CDK2 (IC50 = 91 3.4 466 288 μM). It inhibited proliferation of A375 melanoma cells at 580 nM. Also known as PI3-K Inhibitor 2 PIK2.References Powered by Bioz See more details on Bioz1) M. Hayakawa et al. "Synthesis and biological evaluation of 4-morpholino-2-phenyl quinazolines and related derivatives as novel PI3 kinase p110a inhibitors" Bioorg. Med. Chem. 2006 14 6847-6858.

IC87114 is a specific inhibitor of PI 3-kinase δ (IC50 = 0.5 μM) with >60-fold selectivity over other isoforms (IC50: α = >100 μM β = 75 μM γ = 29 μM). It does not inhibit other protein kinases (p38MAPK CHK1 cSrc PKBα CK1 PKCα PKCβII) at 10 uM. PI 3-K &delta has an important role in inflammation and inhibition has been shown to impair neutrophil migration. Administration of IC87114 in a mouse asthma model decreased allergic airway inflammation.Publications Powered by Bioz See more details on Bioz

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