Discovery of a novel class of AKT pleckstrin homology domain inhibitors

Daruka Mahadevan, Garth Powis, Eugene A. Mash, Benjamin George, Vijay Gokhale, Shuxing Zhang, Kishore Shakalya, Lei Du-Cuny, Margareta Berggren, M. Ahad Ali, Umasish Jana, Nathan Ihle, Sylvestor Moses, Chloe Franklin, Satya Narayan, Nikhil Shirahatti, Emmanuelle Meuillet

Research output: Contribution to journalArticlepeer-review

65 Scopus citations


AKT, a phospholipid-binding serine/threonine kinase, is a key component of the phosphoinositide 3-kinase cell survival signaling pathway that is aberrantly activated in many human cancers. Many attempts have been made to inhibit AKT; however, selectivity remains to be achieved. We have developed a novel strategy to inhibit AKT by targeting the pleckstrin homology (PH) domain. Using in silico library screening and interactive molecular docking, we have identified a novel class of non-lipid-based compounds that bind selectively to the PH domain of AKT, with "in silico" calculated KD values ranging from 0.8 to 3.0 μmol/L. In order to determine the selectivity of these compounds for AKT, we used surface plasmon resonance to measure the binding characteristics of the compounds to the PH domains of AKT1, insulin receptor substrate-1, and 3-phosphoinositide-dependent protein kinase 1. There was excellent correlation between predicted in silico and measured in vitro KDs for binding to the PH domain of AKT, which were in the range 0.4 to 3.6 μmol/L. Some of the compounds exhibited PH domain-binding selectivity for AKT compared with insulin receptor substrate-1 and 3-phosphoinositide-dependent protein kinase 1. The compounds also inhibited AKT in cells, induced apoptosis, and inhibited cancer cell proliferation. In vivo, the lead compound failed to achieve the blood concentrations required to inhibit AKT in cells, most likely due to rapid metabolism and elimination, and did not show antitumor activity. These results show that these compounds are the first small molecules selectively targeting the PH domain of AKT.

Original languageEnglish (US)
Pages (from-to)2621-2632
Number of pages12
JournalMolecular Cancer Therapeutics
Issue number9
StatePublished - 2008

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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