Rare Streptomyces sp. polyketides as modulators of K-Ras localisation

Angela A. Salim, Xue Xiao, Kwang Jin Cho, Andrew M. Piggott, Ernest Lacey, John F. Hancock, Robert J. Capon*

*Corresponding author for this work

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

Chemical investigations of a soil-derived Streptomyces sp. led to the isolation of five new polyketides, (+)-oxanthromicin, (±)-hemi- oxanthromicins A/B, (±)-spiro-oxanthromicin A and oxanthroquinone, and the known alkaloid staurosporine, and the detection of four new metastable analogues, (±)-spiro-oxanthromicins B1/B2/C1/C2. Among the compounds tested, SAR investigations established that the synthetic oxanthroquinone ethyl ester and 3-O-methyl-oxanthroquinone ethyl ester were optimal at mislocalising oncogenic mutant K-Ras from the plasma membrane of intact Madin-Darby canine kidney (MDCK) cells (IC50 4.6 and 1.2 μM), while a sub-EC 50 dose of (±)-spiro-oxanthromicin A was optimal at potentiating (750%) the K-Ras inhibitory activity of staurosporine (IC 50 60 pM). These studies demonstrate that a rare class of Streptomyces polyketide modulates K-Ras plasma membrane localisation, with implications for the future treatment of K-Ras dependent cancers. This journal is

Original languageEnglish
Pages (from-to)4872-4878
Number of pages7
JournalOrganic and Biomolecular Chemistry
Volume12
Issue number27
DOIs
Publication statusPublished - 21 Jul 2014

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