PP121 is a dual inhibitor of receptor tyrosine kinases (RTKs) (IC50 < 0.02 μM for Abl, Src, VEGFR-2 and PDGFR) and PI 3-K family kinases (IC50 < 0.06 μM for p110α, DNA-PK and mTOR). PP121 is the first inhibitor active on both Tyrosine kinases and the phosphatidylinositol-3-OH kinase (PI(3)K) family. PP121 blocks the proliferation of tumor cells by direct inhibition of PI 3-K, mTOR, Src and the VEGF receptor. PP-121 induces a G0/G1 arrest in LN220, U87 and Seg1 cells. PP-121 directly inhibits Bcr-Abl induced tyrosine phosphorylation, resulting in drug-induced apoptosis in K562 cells and a combination of apoptosis and cell cycle arrest in Bcr-Abl expressing BaF3 cells. PP-121 also inhibits other PI3Ks including p110α and DNA-PK with IC50 of 52 nM and 60 nM, respectively.
|Cell lines||U87 and LN229 cells line|
|Preparation method||Cell proliferation assays.
Cells grown in 96-well plates were treated with inhibitor at 4-fold dilutions (10 µM - 0.040 μM) or vehicle (0.1% DMSO). After 72 h cells were exposed to Resazurin sodium salt (22 µM, Sigma) and fluorescence was quantified. IC50 values were calculated using Prism software. For proliferation assays involving single cell counting, non-adherent cells were plated at low density (3–5% confluence) and treated with drug (2.5 µM) or vehicle (0.1% DMSO). Cells were diluted into trypan blue daily and viable cells counted using a hemocytometer.
|Concentrations||10 µM - 0.040 μM|
|Incubation time||72 h|
|Animal models||Eca-109 cells Mice xenograft|
|Formulation||10% 1-methyl-2-pyrrolidinone and 90% PEG 300|
|Dosages||30 mg/kg daily for 30 days|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
|Solubility||DMSO 60 mg/mL|
The anti-esophageal cancer cell activity by a novel tyrosine/phosphoinositide kinase inhibitor PP121.
Peng Y, et al. Biochem Biophys Res Commun. 2015 Sep 11;465(1):137-44. PMID: 26235881.
Targeted polypharmacology: discovery of dual inhibitors of tyrosine and phosphoinositide kinases.
Apsel B, et al. Nat Chem Biol. 2008 Nov;4(11):691-9. PMID: 18849971.
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