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 PHT-427

PHT-427 is an AKT inhibitor that inhibits AKT and PDPK1 at low micromolar concentrations in numerous cancer cell lines and exhibits good oral anti-tumor activity in mouse xenograft models.  PHT-427 reduces the phosphorylation of AKT and PDPK1. Following the administration of a single oral dose of PHT-427 to mice bearing BxPC-3 human pancreatic tumor xenografts, PHT-427 inhibited the phosphorylation of both Akt and PDPK1 as well as downstream targets maximally at 8–12 h after administration corresponding to its peak plasma concentration, with PDPK1 inhibition extending to 24 hr. Anti-tumor activity was observed in a number of human tumor xenografts with in some cases complete cessation of tumor growth during administration of the compound and some tumor regressions observed. Mutational profiles indicate that EGFR and PIK3CA activiating mutations provide greatest sensitivity to PHT-427. Pre-clinical development of PHT-427 continues.

Current developer: PHusis Therapeutics Inc.

PHT-427 was found to bound with the highest affinity to the PH domains of both PDPK1 and Akt. PHT-427 inhibited Akt and PDPK1 signaling and their downstream targets in sensitive but not resistant cells and tumor xenografts. When given orally, PHT-427 inhibited the growth of human tumor xenografts in immunodeficient mice, with up to 80% inhibition in the most sensitive tumors, and showed greater activity than analogues with C4, C6, or C8 alkyl chains. Inhibition of PDPK1 was more closely correlated to antitumor activity than Akt inhibition. Tumors with PIK3CA mutation were the most sensitive, and K-Ras mutant tumors were the least sensitive. Combination studies showed that PHT-427 has greater than additive antitumor activity with paclitaxel in breast cancer and with erlotinib in non-small cell lung cancer. When given >5 days, PHT-427 caused no weight loss or change in blood chemistry. Thus, we report a novel PH domain binding inhibitor of PDPK1/Akt signaling with significant in vivo antitumor activity and minimal toxicity.  (source: Mol Cancer Ther. 2010 Mar;9(3):706-17.)

1: Meuillet EJ, Zuohe S, Lemos R, Ihle N, Kingston J, Watkins R, Moses SA, Zhang  S, Du-Cuny L, Herbst R, Jacoby JJ, Zhou LL, Ahad AM, Mash EA, Kirkpatrick DL, Powis G. 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. Epub 2010 Mar 2. PubMed PMID: 20197390; PubMed Central PMCID: PMC2837366.

2: Moses SA, Ali MA, Zuohe S, Du-Cuny L, Zhou LL, Lemos R, Ihle N, Skillman AG, Zhang S, Mash EA, Powis G, Meuillet EJ. 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. Epub 2009 Jun 2. PubMed PMID: 19491272; PubMed Central PMCID: PMC2914301.