Background:

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]

参考文献:
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.