Synthetic bryostatin analogues activate the RasGRP1 signaling pathway

James C. Stone, Stacey L. Stang, Yong Zheng, Nancy A. Dower, Stacey E. Brenner, Jeremy L. Baryza, Paul A. Wender

Research output: Contribution to journalArticle

21 Scopus citations

Abstract

The functional properties of four diacylglycerol (DAG) analogues were compared using cell-signaling assays based on the protein RasGRP1, a DAG-regulated Ras activator. Compounds 1 and 2, synthetic analogues of bryostatin 1, were compared to authentic bryostatin 1 and phorbol 12-myristate-13-acetate (PMA). The two "bryologues" were able to activate RasGRP1 signaling rapidly in cultured cells and isolated mouse thymocytes. They elicited expression of the T cell activation marker CD69 in human T cells. DAG analogues promptly recruited RasGRP1 to cell membranes, but they did not induce RasGRP1 proteolysis. Bryostatin 1 and compounds 1 and 2 appeared to be less potent than PMA at inducing aggregation of mouse thymocytes, a PKC-dependent, RasGRP1-independent response. In addition to sharing potential anticancer properties with bryostatin 1, compounds 1 and 2 might be clinically useful as modulators of the immune system.

Original languageEnglish (US)
Pages (from-to)6638-6644
Number of pages7
JournalJournal of medicinal chemistry
Volume47
Issue number26
DOIs
StatePublished - Dec 16 2004
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery

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  • Cite this

    Stone, J. C., Stang, S. L., Zheng, Y., Dower, N. A., Brenner, S. E., Baryza, J. L., & Wender, P. A. (2004). Synthetic bryostatin analogues activate the RasGRP1 signaling pathway. Journal of medicinal chemistry, 47(26), 6638-6644. https://doi.org/10.1021/jm0495069