PHT-427 is a novel small-molecule inhibitor of PDPK1/Akt signaling with significant antitumor activity and minimal toxicity in vivo. The phosphatidylinositol 3-kinase/AKT signaling pathway plays a critical role in activating survival and antiapoptotic pathways within cancer cells. PHT-427 binds selectively to the PH domain of AKT, causing apoptosis at low micromolar concentrations. And it also binds to the PH domain of PDPK1. PHT-427 inhibited Akt and PDPK1 signaling and their downstream targets in sensitive but not resistant cells and tumor xenografts. PHT-427 induces apoptosis (IC50 = 6.3 μM), mainly on Akt Ser473 residue and less strongly on the Akt Thr308 residue without affecting total Akt protein expression. PHT-427 also shows antiproliferation in Panc-1 cells (IC50 = 65 μM).
|Cell lines||Human MiaPaCa-2, BxPC-3, and Panc-1 pancreatic cancer cells|
|Preparation method||Cell cytotoxicity assay
Cell growth inhibition was determined using a micro-cytoxicity assay. Cells were plated in 96-well micro-cytoxicity at 5,000–10,000 cells per well (depending on cell doubling time) and grown for 7 days. Compounds dissolved in DMSO were added directly to the media, at various concentrations ranging from 1 to 50 μM. The endpoint was spectrophotometric determination of the protein content of each well using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide. A concentration-response relationship at two or more concentration levels was used to obtain an IC50 for the compound.
|Incubation time||48 h|
|Animal models||BxPC-3, Panc-1, MiaPaCa-2, PC-3, SKOV-3, A-549 or MCF-7 cells tumour model in female scid mice|
|Formulation||40 to 50 mg/ml in sesame seed oil|
|Dosages||200 mg/kg twice daily for 10 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 80 mg/mL|
Molecular pharmacology and antitumor activity of PHT-427, a novel Akt/phosphatidylinositide-dependent protein kinase 1 pleckstrin homology domain inhibitor.
Meuillet EJ, et al. Mol Cancer Ther. 2010 Mar;9(3):706-17. PMID: 20197390.
In vitro and in vivo activity of novel small-molecule inhibitors targeting the pleckstrin homology domain of protein kinase B/AKT.
Moses SA, et al. Cancer Res. 2009 Jun 15;69(12):5073-81. PMID: 19491272.
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