Microbial K-Ras Inhibitors

Small molecules known to modulate biological activies of the K-Ras oncogene are predominantly of synthetic origin (ex. Salirasib). Nevetheless, various publications have recently demontrated the biological potential of microbial metabolites in KRAS studies. Here’s a good opportunity to briefly review a few of these compounds.

By screening a microbial extract library in a high content cell-based assay, Salim et al. identified Oligomycins A, B, C, D, E and 21-hydroxyoligomycin A as potent specific inhibitors of K-Ras plasma membrane (PM) localisation. The Oligomycin rare microbial extracts have shown to be cytotoxic to human colorectal carcinoma cells inhibiting also the ABC transporter efflux pump P-glycoprotein (P-gp). (1)

Salinomycin is one of the most established Cancer Stem Cell (CSC) inhibitor interfering with K-ras membrane organization. Using a smart K-ras-specific screening platform, Najumudeen AK et al. identified Conglobatin A, Ophiobolin A, Avermectin & Ivermectin, Kazusamycin B, Leptomycin B and Streptonigrin as new promising candidate CSC inhibitors. In this study, Ophiobolin A was the most potent compound, exerting its activity on K-Ras4B through interaction with Calmodulin, suggesting selective inhibition of CSCs. (2) These new discoveries regarding K-Ras and microbial metabolites complement previous observations showing that Antimycins/Rotenone significantly reduced oxygen consumption of K-Ras expressing (+KRas) and surviving (-KRas) Pancreatic Ductal Adenocarcinoma Cells (PDAC). (3)

References:

1. Salim A.A. et al. Oligomycins as inhibitors of K-Ras plasma membrane localisation. Org. Biomol. Chem. 2016; 14(2): 711-715. DOI : 10.1039/c5ob02020d.
2. Najumudeen A.K. et al. Cancer stem cell druges target K-ras signalling in a stemness context. Oncogene 2016: 1-15.  DOI: 10.1038/onc.2016.59.
3. Viale A. et al. Oncogene ablation-resistant pancreatic cancer cells depend on mitochondrial function. Nature 2014; 514(7254); 628 – 632. DOI: 10.1038/nature13611.

Thank you to our friends from Bioaustralis for providing us with this update regarding K-Ras inhibitors.

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