PHT-427

本公司产品仅用于科研实验，不得用于人体或动物的临床与诊断

PHT-427 是一种小分子 Akt 抑制剂，选择性结合 AKT 的 PH 结构域，Ki 为 2.4 uM。

PHT-427 is a small-molecule Akt inhibitor that binds selectively to the PH domain of AKT with Ki of 2.4 uM, inhibits phospho-Ser473-AKT in Panc-1 cells with IC50 of 6.3 uM; decreases AKT activation and causes apoptosis at low micromolar concentrations in Panc-1 and MiaPaCa-2 pancreatic cancer cell lines; inhibits AKT and its downstream targets in cells, exhibits good antitumor activity in pancreatic cancer cell xenografts in immunocompromised mice.

The effects of PHT-427 on cell signaling are investigated by RPPA using a panel of 86 antibodies to phospho- and non-phosphorylated signaling protein related to PtdIns-3-K/PDPK1/Akt signaling in PC-3 prostate cells where PtdIns-3-K/PDPK1/Akt signaling is activated because of homozygous PTEN mutation. After 16 hours, a reduction is observed in phospho-Ser241-PDPK1 phospho-Thr308-Akt by both 10 μM PH-427 and 0.1 μM Wortmannin. Finally, phospho-Ser657-protein kinase C (PKC) and total SGK1 are decreased by treatment with both PHT-427 and Wortmannin. These results suggest that at 10 μM PHT-427 inhibits both Akt and PDKP1. The BxPC-3 and MiaPaCa-2 pancreatic cancer cell lines are probed by Western blotting following up to 24 hr exposure to 10 μM PHT-427, which is below the IC50 for cell growth inhibition of around 30 μM, to determine the effects of PHT-427 on of the PtdIns-3-K/PDPK1/Akt signaling pathway components.

Mice with BxPC-3 pancreatic, MCF-7 breast or A-549 NSCL cancer xenografts are administered PHT-427, or its analogs with a C-4, C-6 or C-8 alkyl chain by oral gavage twice a day for 10 days. The results show that PHT-427 has the greatest antitumor activity with the C-8 chain analog having less activity, and analogs with a C-4 or C-6 chain very little activity. All further antitumor studies are conducted using compound PHT-427. Plasma levels of PHT-427 following oral administration to mice of a dose of 200 mg/kg show rapid absorption, without a lag phase, Cmax is 8.2 μg/mL 1 hr following dosing, and the elimination half-life is 1.4 hr with a terminal PHT-427 concentration of 0.1 μg/mL 10 hr after dosing. The plasma concentration of PH-427 is above the level which gave inhibition of Akt and PDPK1 signaling in cells of 10 μM (4 μg/mL) for at least 3 hr.

PHT 427 | PHT427

Cytoskeleton/Cell Adhesion Molecules

Akt

Akt|PDK1

Cancer

——

1191951-57-1

409.609

C20H31N3O2S2

>98% (HPLC)

10 mM in DMSO

O=S(C1=CC=C(CCCCCCCCCCCC)C=C1)(NC2=NN=CS2)=O

Benzenesulfonamide, 4-dodecyl-N-1,3,4-thiadiazol-2-yl-

(-20℃)

With Ice Pack

≥ 2 years