1. Academic Validation
  2. Small molecule-induced cytosolic activation of protein kinase Akt rescues ischemia-elicited neuronal death

Small molecule-induced cytosolic activation of protein kinase Akt rescues ischemia-elicited neuronal death

  • Proc Natl Acad Sci U S A. 2012 Jun 26;109(26):10581-6. doi: 10.1073/pnas.1202810109.
Hakryul Jo 1 Subhanjan Mondal Dewar Tan Eiichiro Nagata Shunya Takizawa Alok K Sharma Qingming Hou Kumaran Shanmugasundaram Amit Prasad Joe K Tung Alexander O Tejeda Hengye Man Alan C Rigby Hongbo R Luo
Affiliations

Affiliation

  • 1 Department of Pathology, Harvard Medical School, Dana-Farber/Harvard Cancer Center, Boston, MA 02115, USA.
Abstract

Elevating Akt activation is an obvious clinical strategy to prevent progressive neuronal death in neurological diseases. However, this endeavor has been hindered because of the lack of specific Akt activators. Here, from a cell-based high-throughput chemical genetic screening, we identified a small molecule SC79 that inhibits Akt membrane translocation, but paradoxically activates Akt in the cytosol. SC79 specifically binds to the PH domain of Akt. SC79-bound Akt adopts a conformation favorable for phosphorylation by upstream protein kinases. In a hippocampal neuronal culture system and a mouse model for ischemic stroke, the cytosolic activation of Akt by SC79 is sufficient to recapitulate the primary cellular function of Akt signaling, resulting in augmented neuronal survival. Thus, SC79 is a unique specific Akt Activator that may be used to enhance Akt activity in various physiological and pathological conditions.

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