Oligomycins as inhibitors of K-Ras plasma membrane localisation

A. A. Salim, L. Tan, X.-C. Huang, K.-J. Cho, E. Lacey, J. F. Hancock and R. J. Capon

Oligomycins as inhibitors of K-Ras plasma membrane localisation

Publication Date:  November 4, 2015



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).

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21-hydroxy-oligomycin A

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