title: Deactivation of Akt by a small molecule inhibitor targeting pleckstrin homology domain and facilitating Akt ubiquitination.
abstract: The phosphatidylinositol-3,4,5-triphosphate (PIP3) binding function of pleckstrin homology (PH) domain is essential for the activation of oncogenic Akt/PKB kinase. Following the PIP3-mediated activation at the membrane, the activated Akt is subjected to other regulatory events, including ubiquitination-mediated deactivation. Here, by identifying and characterizing an allosteric inhibitor, SC66, we show that the facilitated ubiquitination effectively terminates Akt signaling. Mechanistically, SC66 manifests a dual inhibitory activity that directly interferes with the PH domain binding to PIP3 and facilitates Akt ubiquitination. A known PH domain-dependent allosteric inhibitor, which stabilizes Akt, prevents the SC66-induced Akt ubiquitination. A cancer-relevant Akt1 (e17k) mutant is unstable, making it intrinsically sensitive to functional inhibition by SC66 in cellular contexts in which the PI3K inhibition has little inhibitory effect. As a result of its dual inhibitory activity, SC66 manifests a more effective growth suppression of transformed cells that contain a high level of Akt signaling, compared with other inhibitors of PIP3/Akt pathway. Finally, we show the anticancer activity of SC66 by using a soft agar assay as well as a mouse xenograft tumor model. In conclusion, in this study, we not only identify a dual-function Akt inhibitor, but also demonstrate that Akt ubiquitination could be chemically exploited to effectively facilitate its deactivation, thus identifying an avenue for pharmacological intervention in Akt signaling.
authors.affiliation: Department of Pathology, Harvard Medical School, Dana-Farber/Harvard Cancer Center, Boston, MA 02115, USA.
authors.forename: Hakryul
authors.initials: H
authors.lastname: Jo
authors.forename: Pang-Kuo
authors.initials: PK
authors.lastname: Lo
authors.forename: Yitang
authors.initials: Y
authors.lastname: Li
authors.forename: Fabien
authors.initials: F
authors.lastname: Loison
authors.forename: Sarah
authors.initials: S
authors.lastname: Green
authors.forename: Jake
authors.initials: J
authors.lastname: Wang
authors.forename: Leslie E
authors.initials: LE
authors.lastname: Silberstein
authors.forename: Keqiang
authors.initials: K
authors.lastname: Ye
authors.forename: Hexin
authors.initials: H
authors.lastname: Chen
authors.forename: Hongbo R
authors.initials: HR
authors.lastname: Luo
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects / Q000235:genetics; D019943:Amino Acid Substitution; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D003512:Cyclohexanones / Q000737:chemistry / Q000494:pharmacology*; D005260:Female; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D020125:Mutation, Missense; D010716:Phosphatidylinositols / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D017434:Protein Structure, Tertiary; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D054875:Ubiquitination / Q000187:drug effects* / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D003512:Cyclohexanones; D010716:Phosphatidylinositols; D047428:Protein Kinase Inhibitors; D011725:Pyridines; C000598518:SC-66 compound; C118303:phosphoinositide-3,4,5-triphosphate; C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt