Neristatin 1 provides critical insight into bryostatin 1 structure-function relationships.

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Kedei N, Kraft MB, Keck GE, Herald CL, Melody N, Pettit GR, Blumberg PM

Neristatin 1 provides critical insight into bryostatin 1 structure-function relationships.

J Nat Prod. 2015 Apr 24;78(4):896-900. doi: 10.1021/acs.jnatprod.5b00094. Epub 2015 Mar 26.

PubMed ID

25808573 [ View in PubMed

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Abstract

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.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Bryostatin 1	Tumor necrosis factor	Protein	Humans	Unknown	Inducer	Details