Molecular pharmacology and antitumor activity of PHT-427, a novel akt/phosphatidylinositide-dependent protein kinase 1 pleckstrin homology domain inhibitor

Emmanuelle J. Meuillet, Song Zuohe, Robert Lemos, Nathan Ihle, John Kingston, Ryan Watkins, Sylvestor A. Moses, Shuxing Zhang, Lei Du-Cuny, Roy Herbst, Jörg J. Jacoby, Li Li Zhou, Ali M. Ahad, Eugene A. Mash, D. Lynn Kirkpatrick, Garth Powis

Research output: Contribution to journalArticle

46 Scopus citations

Abstract

Phosphatidylinositol 3-kinase/phosphatidylinositide-dependent protein kinase 1 (PDPK1)/Akt signaling plays a critical role in activating proliferation and survival pathways within cancer cells. We report the molecular pharmacology and antitumor activity of PHT-427, a compound designed to bind to the pleckstrin homology (PH) binding domain of signaling molecules important in cancer. Although originally designed to bind the PH domain of Akt, we now report that PHT-427 also binds to the PH domain of PDPK1. A series of PHT-427 analogues with variable C-4 to C-16 alkyl chain length were synthesized and tested. 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 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.

Original languageEnglish (US)
Pages (from-to)706-717
Number of pages12
JournalMolecular Cancer Therapeutics
Volume9
Issue number3
DOIs
StatePublished - Mar 2010

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Meuillet, E. J., Zuohe, S., Lemos, R., Ihle, N., Kingston, J., Watkins, R., Moses, S. A., Zhang, S., Du-Cuny, L., Herbst, R., Jacoby, J. J., Zhou, L. L., Ahad, A. M., Mash, E. A., Kirkpatrick, D. L., & Powis, G. (2010). Molecular pharmacology and antitumor activity of PHT-427, a novel akt/phosphatidylinositide-dependent protein kinase 1 pleckstrin homology domain inhibitor. Molecular Cancer Therapeutics, 9(3), 706-717. https://doi.org/10.1158/1535-7163.MCT-09-0985