title: Oligomycins as inhibitors of K-Ras plasma membrane localisation.
abstract: Frequently present in pancreatic, colorectal and non-small cell lung carcinomas, oncogenic mutant K-Ras must be localised to the plasma membrane (PM) to be functional. Inhibitors of K-Ras PM localisation are therefore putative cancer chemotherapeutics. By screening a microbial extract library in a high content cell-based assay we detected the rare oligomycin class of Streptomyces polyketides as inhibitors of K-Ras PM localisation. Cultivation and fractionation of three unique oligomycin producing Streptomyces strains yielded oligomycins A-E (1-5) and 21-hydroxy-oligomycin A (6), together with the new 21-hydroxy-oligomycin C (7) and 40-hydroxy-oligomycin B (8). Structures for 1-8 were assigned by detailed spectroscopic analysis. Cancer cell viability screening confirmed 1-8 were cytotoxic to human colorectal carcinoma cells (IC50 > 3 μM), and were inhibitors of the ABC transporter efflux pump P-glycoprotein (P-gp), with 5 being comparable in potency to the positive control verapamil. Significantly, oligomycins 1-8 proved to be exceptionally potent inhibitors of K-Ras PM localisation (Emax 0.67-0.75 with an IC50 ~ 1.5-14 nM).
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, St Lucia, QLD 4072, Australia. r.capon@uq.edu.au.
authors.forename: A A
authors.initials: AA
authors.lastname: Salim
authors.forename: L
authors.initials: L
authors.lastname: Tan
authors.forename: X-C
authors.initials: XC
authors.lastname: Huang
authors.forename: K-J
authors.initials: KJ
authors.lastname: Cho
authors.forename: E
authors.initials: E
authors.lastname: Lacey
authors.forename: J F
authors.initials: JF
authors.lastname: Hancock
authors.forename: R J
authors.initials: RJ
authors.lastname: Capon
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000187:drug effects* / Q000201:enzymology*; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000201:enzymology / Q000473:pathology; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D006801:Humans; D061985:Madin Darby Canine Kidney Cells; D009840:Oligomycins / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D021381:Protein Transport / Q000187:drug effects; D013329:Structure-Activity Relationship; D018631:ras Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D009840:Oligomycins; D018631:ras Proteins