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Neristatin 1 Provides Critical Insight into Bryostatin 1 Structure–Function Relationships

[Image: see text] Bryostatin 1, a complex macrocyclic lactone isolated from Bugula neritina, has been the subject of multiple clinical trials for cancer. Although it functions as an activator of protein kinase C (PKC) in vitro, bryostatin 1 paradoxically antagonizes most responses to the prototypica...

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Detalles Bibliográficos
Autores principales: Kedei, Noemi, Kraft, Matthew B., Keck, Gary E., Herald, Cherry L., Melody, Noeleen, Pettit, George R., Blumberg, Peter M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society and American Society of Pharmacognosy 2015
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4415049/
https://www.ncbi.nlm.nih.gov/pubmed/25808573
http://dx.doi.org/10.1021/acs.jnatprod.5b00094
Descripción
Sumario:[Image: see text] Bryostatin 1, a complex macrocyclic lactone isolated from Bugula neritina, has been the subject of multiple clinical trials for cancer. Although it functions as an activator of protein kinase C (PKC) in vitro, bryostatin 1 paradoxically antagonizes most responses to the prototypical PKC activator, the phorbol esters. The bottom half of the bryostatin 1 structure has been shown to be sufficient to confer binding to PKC. In contrast, we have previously shown that the top half of the bryostatin 1 structure is necessary for its unique biological behavior to antagonize phorbol ester responses. Neristatin 1 comprises a top half similar to that of bryostatin 1 together with a distinct bottom half that confers PKC binding. We report here that neristatin 1 is bryostatin 1-like, not phorbol ester-like, in its biological activity on U937 promyelocytic leukemia cells. We conclude that the top half of the bryostatin 1 structure is largely sufficient for bryostatin 1-like activity, provided the molecule also possesses an appropriate PKC binding domain.