ABSTRACT
[This corrects the article DOI: 10.1038/s41540-019-0112-5.].
ABSTRACT
Eukaryotic genetic interaction networks (GINs) are extensively described in the Saccharomyces cerevisiae S288C model using deletion libraries, yet being limited to this one genetic background, not informative to individual drug response. Here we created deletion libraries in three additional genetic backgrounds. Statin response was probed with five queries against four genetic backgrounds. The 20 resultant GINs representing drug-gene and gene-gene interactions were not conserved by functional enrichment, hierarchical clustering, and topology-based community partitioning. An unfolded protein response (UPR) community exhibited genetic background variation including different betweenness genes that were network bottlenecks, and we experimentally validated this UPR community via measurements of the UPR that were differentially activated and regulated in statin-resistant strains relative to the statin-sensitive S288C background. These network analyses by topology and function provide insight into the complexity of drug response influenced by genetic background.
Subject(s)
Gene Regulatory Networks/genetics , Hydroxymethylglutaryl-CoA Reductase Inhibitors/metabolism , Saccharomyces cerevisiae/genetics , Biomarkers, Pharmacological , Cluster Analysis , Drug Resistance/genetics , Drug Resistance/physiology , Epistasis, Genetic/genetics , Gene Expression Regulation, Fungal/drug effects , Gene Expression Regulation, Fungal/genetics , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology , Models, Genetic , Saccharomyces cerevisiae Proteins/genetics , Unfolded Protein Response/genetics , Unfolded Protein Response/physiologyABSTRACT
A series of N,N-bis(glycityl)amines with promising anti-cancer activity were prepared via the reductive amination of pentoses and hexoses, and subsequently screened for their ability to selectively inhibit the growth of cancerous versus non-cancerous cells. For the first time, we show that this class of compounds possesses anti-proliferative activity, and, while the selective killing of brain cancer (LN18) cells versus matched (SVG-P12) cells was modest, several of the amines, including d-arabinitylamine 1a and d-fucitylamine 1g, exhibited low micromolar IC50 values for HL60 cells. Moreover, these two amines showed good selectivity towards HL60 cells when compared to non-cancerous HEK-293 cells. The compounds also showed low micromolar inhibition of the leukaemic cell line, THP-1. The modes of action of amines 1a and 1g were then determined using yeast chemical genetics, whereby it was established that both compounds affect similar but distinct sets of biochemical pathways. Notably purine nucleoside monophosphate biosynthesis was identified as an enriched mechanism. The rapid synthesis of the amines and their unique mode of action thus make them attractive targets for further development as anti-cancer drugs.
