Oligomycins as inhibitors of K-Ras plasma membrane localisation

Salim, A. A., Tan, L., Huang, X. C., Cho, K. J., Lacey, E., Hancock, J. F. and Capon, R. J. (2015) Oligomycins as inhibitors of K-Ras plasma membrane localisation. Organic and Biomolecular Chemistry, 14 2: 711-715. doi:10.1039/c5ob02020d

Author Salim, A. A.
Tan, L.
Huang, X. C.
Cho, K. J.
Lacey, E.
Hancock, J. F.
Capon, R. J.
Title Oligomycins as inhibitors of K-Ras plasma membrane localisation
Journal name Organic and Biomolecular Chemistry   Check publisher's open access policy
ISSN 1477-0520
Publication date 2015-11-13
Sub-type Article (original research)
DOI 10.1039/c5ob02020d
Open Access Status Not Open Access
Volume 14
Issue 2
Start page 711
End page 715
Total pages 5
Place of publication Cambridge, United Kingdom
Publisher Royal Society of Chemistry
Collection year 2016
Language eng
Formatted 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).
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2016 Collection
Institute for Molecular Bioscience - Publications
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Created: Wed, 09 Dec 2015, 08:57:23 EST by Susan Allen on behalf of Institute for Molecular Bioscience