Phosphatidylinositol 3-kinase (PIK3)/PtdIns dependent protein kinase-1(PDPK1)/Akt signaling plays a critical role in activating proliferation and survival pathways within cancer cells. PHT-427 is a compound designed to bind to the pleckstrin homology (PH) binding domain of signaling molecules. PHT-427 itself (C-12 chain) bound with the highest affinity to the PH domains of both PDPK1 and Akt. PHT-427 inhibited Akt and PDKP1 signaling and their downstream targets in sensitive but not resistant cells and tumor xenografts. The Ki values of PHT-427 are 2.7 and 5.2 µM towards Akt and PDPK1 respectively. RPPA studies in PC-3 prostate cancer cells showed that PHT-427 caused a reduction in phospho-Thr308-Akt, and also in phospho-Ser241-PDPK1 and its downstream targets, phospho-Ser657-PKC and total SGK1. In vivo studies in mice with BxPC-3 and MiaPaCa-2 xenografts treated with a 200 mg/kg dose of PHT-427 showed a decrease in phospho-Ser473-AKT, phospho-Thr308-Akt, phospho-Ser241-PDPK1 and in the PDKP1-specific downstream target phospho-Ser221-RSK[5].
PHT-427 细胞实验
Cell Line
Concentration
Treated Time
Description
References
BxPC-3 pancreatic cancer cells
10 µM
12-16 hours
Inhibition of Akt and PDKP1 signaling and their downstream targets
Mol Cancer Ther. 2010 Mar;9(3):706-17.
MiaPaCa-2 pancreatic cancer cells
10 µM
12-16 hours
No significant inhibition of Akt and PDKP1 signaling
Mol Cancer Ther. 2010 Mar;9(3):706-17.
HaCaT human keratinocytes
100 nM
24 hours
To investigate the effect of rapamycin on Akt signaling and test whether PHT-427 could block these effects. Results showed that rapamycin increased Akt (S473) phosphorylation, and PHT-427 significantly reduced rapamycin-induced Akt (S473) phosphorylation.
Cancer Prev Res (Phila). 2016 Mar;9(3):215-24.
FaDu cells
0.5, 0.75, 1 mg/mL
24 or 48 hours
To evaluate the effect of PHT-427-loaded nanoparticles on the proliferation and apoptosis of FaDu cells. Results showed that PHT-427 significantly enhanced its antiproliferative and proapoptotic activity by inactivating the PI3K/AKT/PDK1 pathway, inducing apoptosis.
Pharmaceutics. 2021 Aug 12;13(8):1242.
Panc-1 pancreatic cancer cells
1, 5, 10 µM
4 hours
Inhibition of subcellular localization of Akt and PDKP1
Mol Cancer Ther. 2010 Mar;9(3):706-17.
PHT-427 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Nude mice
Xenograft model
IntratumOral injection
0.5 mg/ml and 1 mg/ml
Once a week for four weeks
To evaluate the anticancer efficacy of PHT-427 in head and neck squamous cell carcinoma, results showed that PHT-427 encapsulation increased drug efficacy and safety, as demonstrated by decreased tumor volume, reduced PI3K/AKT/PDK1 pathway expression, and improved antitumor activity and necrosis induction.
Drug Deliv. 2025 Dec;32(1):2449376
Mice
Immunodeficient mice
Oral
125-250 mg/kg
Twice a day for 10 days
Inhibited the growth of human tumor xenografts with up to 80% inhibition in the most sensitive tumors
Mol Cancer Ther. 2010 Mar;9(3):706-17.
SKH-1 hairless mice
SSL-induced skin tumor model
Topical administration
3.7 µmol/back
Three times a week for 10 weeks
To investigate the inhibitory effect of PHT-427 combined with rapamycin on SSL-induced skin tumors. Results showed that the combination of PHT-427 and rapamycin significantly reduced tumor multiplicity.
Cancer Prev Res (Phila). 2016 Mar;9(3):215-24.
Mice
MiaPaCa-2 pancreatic cancer model
Intraperitoneal injection
SE-PLGA-427: 14 mg/kg, DE-PLGA-427: 19 mg/kg
Once per week for four weeks
To evaluate the therapeutic effect of PHT-427 in a pancreatic cancer model, the results showed that both SE-PLGA-427 and DE-PLGA-427 significantly reduced tumor volume and eliminated primary pancreatic tumors in 68% of the mice.
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