title: Rare Streptomyces sp. polyketides as modulators of K-Ras localisation.
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-EC50 dose of (±)-spiro-oxanthromicin A was optimal at potentiating (750%) the K-Ras inhibitory activity of staurosporine (IC50 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.
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, St. Lucia, QLD 4072, Australia. r.capon@uq.edu.au.
authors.forename: Angela A
authors.initials: AA
authors.lastname: Salim
authors.forename: Xue
authors.initials: X
authors.lastname: Xiao
authors.forename: Kwang-Jin
authors.initials: KJ
authors.lastname: Cho
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Piggott
authors.forename: Ernest
authors.initials: E
authors.lastname: Lacey
authors.forename: John F
authors.initials: JF
authors.lastname: Hancock
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Capon
mesh_terms: D000818:Animals; D002462:Cell Membrane / Q000737:chemistry; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid; D004285:Dogs; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D061065:Polyketides / Q000737:chemistry / Q000494:pharmacology*; D011518:Proto-Oncogene Proteins / Q000032:analysis*; D016283:Proto-Oncogene Proteins p21(ras); D013302:Streptomyces / Q000378:metabolism*; D013329:Structure-Activity Relationship; D018631:ras Proteins / Q000032:analysis*
chemical_list: C117307:KRAS protein, human; D061065:Polyketides; D011518:Proto-Oncogene Proteins; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins