In vitro and in vivo activity of novel small-molecule inhibitors targeting the pleckstrin homology domain of protein kinase B/AKT

Sylvestor A. Moses, M. Ahad Ali, Song Zuohe, Lei Du-Cuny, Li Zhou Li, Robert Lemos, Nathan Ihle, A. Geoffrey Skillman, Shuxing Zhang, Eugene A. Mash, Garth Powis, Emmanuelle J. Meuillet

Research output: Contribution to journalArticle

39 Scopus citations

Abstract

The phosphatidylinositol 3-kinase/AKT signaling pathway plays a critical role in activating survival and antiapoptotic pathways within cancer cells. Several studies have shown that this pathway is constitutively activated in many different cancer types. The goal of this study was to discover novel compounds that bind to the pleckstrin homology (PH) domain of AKT, thereby inhibiting AKT activation. Using proprietary docking software, 22 potential PH domain inhibitors were identified. Surface plasmon resonance spectroscopy was used to measure the binding of the compounds to the expressed PH domain of AKT followed by an in vitro activity screen in Panc-1 and MiaPaCa-2 pancreatic cancer cell lines. We identified a novel chemical scaffold in several of the compounds that binds selectively to the PH domain of AKT, inducing a decrease in AKT activation and causing apoptosis at low micromolar concentrations. Structural modifications of the scaffold led to compounds with enhanced inhibitory activity in cells. One compound, 4-dodecyl-N-(1,3,4-thiadiazol-2-yl) benzenesulfonamide, inhibited AKT and its downstream targets in cells as well as in pancreatic cancer cell xenografts in immunocompromised mice; it also exhibited good antitumor activity. In summary, a pharmacophore for PH domain inhibitors targeting AKT function was developed. Computer-aided modeling, synthesis, and testing produced novel AKT PH domain inhibitors that exhibit promising preclinical properties.

Original languageEnglish (US)
Pages (from-to)5073-5081
Number of pages9
JournalCancer Research
Volume69
Issue number12
DOIs
StatePublished - Jun 15 2009

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Moses, S. A., Ali, M. A., Zuohe, S., Du-Cuny, L., Li, L. Z., Lemos, R., Ihle, N., Skillman, A. G., Zhang, S., Mash, E. A., Powis, G., & Meuillet, E. J. (2009). In vitro and in vivo activity of novel small-molecule inhibitors targeting the pleckstrin homology domain of protein kinase B/AKT. Cancer Research, 69(12), 5073-5081. https://doi.org/10.1158/0008-5472.CAN-08-3839