Molecular Weight (MW)

254.25

Formula

C12H10N6

CAS No.

925705-73-3

Storage

-20℃ for 3 years in powder form

-80℃ for 2 years in solvent

Solubility (In vitro)

DMSO: 2 mg/mL (7.86 mM)

Water:<1 mg/mL

Ethanol: <1 mg/mL

Other info

Synonym: TG100713; TG-100713; TG 100713

SMILES Code: OC1=CC=CC(C2=NC3=C(N)N=C(N)N=C3N=C2)=C1

Chemical Name

3-(2,4-diaminopteridin-6-yl)phenol

In Vitro

Kinase Assay: PI3K reactions are constructed by using recombinant human kinases, 3 μM ATP, phosphatidylinositol substrate, and cofactors, and reaction progression measured by using a luminescent-based detection system to quantify ATP consumption. Protein kinase assays are performed by using commercial screening services.

Cell Assay: TG 100713 also strongly inhibits EC proliferation. Human umbilical vein EC (HUVEC) plated in 96-well cluster plates (5,000 cells/well) are cultured in assay medium (containing 0.5% serum and 50 ng/ml VEGF) in the presence or absence of test compounds (10 μM), and cell numbers are quantified by XTT assay.

Modeling studies suggested that the freedom of conformational rotation permitted by ring substituents controls isoform selectivity. Although substituent ring of TG100-115, TG100713, and TG101110 all require energy minima at 30–40°, angles diverge of each compound results in paying differing penalties from this range. TG100-115 displays the greatest barrier to rotation and finally is the most isoform selective, TG100713 has the most conformational flexibility (ring A being almost freely rotatable with maxima ≈5 kcal; 1 kcal = 4.18 kJ), suggesting the least selective, and TG101110 lies an intermediate position (several conformations ≦10 but some>>50 kcal)

In Vivo

The minimum structure which satisfies all three requirements is shown in TG100713, which so far has also displayed the best PI3K binding activity. Interestingly, the SAR profiles generating correlate quite well with the results of the initial in vivo screen further supports the involvement of PI3K as a target for inhibiting vascular permeability in related compounds

Animal model

Formulation & Dosage

References

Proc Natl Acad Sci U S A. 2006 Dec 26;103(52):19866-71; J Med Chem. 2007 Sep 6;50(18):4279-94.