{"doi":"10.1073/pnas.1019062108","title":"Deactivation of Akt by a small molecule inhibitor targeting pleckstrin homology domain and facilitating Akt ubiquitination","abstract":"<jats:p>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.</jats:p>","journal":"Proceedings of the National Academy of Sciences","year":2011,"id":683615,"datarank":0.6535063240034389,"base_score":4.356708826689592,"endowment":4.356708826689592,"self_citation_contribution":0.6535063240034389,"citation_network_contribution":0.0,"self_endowment_contribution":0.6535063240034389,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":77,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":10,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":176047,"name":"Pang-Kuo Lo","orcid":null,"position":1,"is_corresponding":false},{"id":1785861,"name":"Yitang Li","orcid":null,"position":2,"is_corresponding":false},{"id":676152,"name":"Fabien Loison","orcid":null,"position":3,"is_corresponding":false},{"id":519264,"name":"Sarah Green","orcid":"0000-0002-0906-2334","position":4,"is_corresponding":false},{"id":1785862,"name":"Jake Wang","orcid":null,"position":5,"is_corresponding":false},{"id":558788,"name":"Leslie E. 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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.</jats:p>","is_dataset_classified":null,"base_score":4.356708826689592,"endowment":4.356708826689592,"datacite_reuse_total":10,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"21464312","pmcid":"PMC3081014","openalex_id":"https://openalex.org/W2159732007","authors":[],"funders":[{"funder_name":"NHLBI NIH HHS","grant_id":"HL066987","title":null},{"funder_name":"NHLBI NIH HHS","grant_id":"HL085100","title":null},{"funder_name":"NIGMS NIH HHS","grant_id":"R01 GM076084","title":null},{"funder_name":"NIGMS NIH HHS","grant_id":"GM076084","title":null},{"funder_name":"NHLBI NIH HHS","grant_id":"HL092020","title":null},{"funder_name":"NIAID NIH 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