Uses
PHT-427 is a dual Akt and PDPK1 inhibitor with Ki of 2.7 μM and 5.2 μM, respectively.
Biological Activity
pht-427 is an inhibitor of akt and pdpk1 (ki =2.7 μm and 5.2 μm, respectively).akt is a serine/threonine-specific protein kinase that plays a vital role in multiple cellular processes including glucose metabolism, apoptosis, cell proliferation, transcription and cell migration etc.in bxpc-3 cells, pht-427 showed inhibition upon akt function with ic50 value of 8.6±0.8 μm and for its downstream substrates. pht-427 reduced the akt phosphorylation on ser473 residue and did not decrease total akt protein level. pht-427 also inhibited p70s6k and gsk3β in a dose-dependent manner. [1][2]in scid (severe combined immunodeficiency) mice of bxpc-3 pancreatic cancer xenografts, administration of pht-427 exerted prominent antitumor activity that halted tumor growth. pht-427 in combination with erlotinib exhibited greater than additive antitumor activity in nsc lung cancer and with paclitaxel in breast cancer. [1][2]
Enzyme inhibitor
This orally bioavailable, dual Akt/PDPK1 inhibitor (F.Wt. = 409.61; CAS 1191951-57-1 and 1178893-77-0; Solubility (25°C): 80 mg/mL DMSO, <1 mg/mL Water), known systematically as 4-dodecyl-N-(1,3,4-thiadiazol-2- yl)benzenesulfonamide, targets Akt (also known as Protein Kinase B, or PKB) and 3-phosphoinositide-dependent protein kinase-1, with Ki of 2.7 μM and 5.2 μM, respectively. PHT-427 was designed to bind to the pleckstrin homology (PH) auto-inhibitory domains of the signal cascade protein kinase Akt.
in vivo
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[1].
References
1. meuillet ej, zuohe s, lemos r et al. molecular pharmacology and antitumor activity of pht-427, a novel akt/phosphatidylinositide-dependent protein kinase 1 pleckstrin homology domain inhibitor. mol cancer ther. 2010 mar;9(3):706-17.2. moses sa, ali ma, zuohe s et al. in vitro and in vivo activity of novel small-molecule inhibitors targeting the pleckstrin homology domain of protein kinase b/akt. cancer res. 2009 jun 15;69(12):5073-81.
