Page 16 - I. Chemical biology and drug discovery

[I. Chemical biology and drug discovery-8]

Identification of unanticipated human targets of antibiotics

Artesunate and Daptomycin for anti-cancer drug

repositioning

Sung Min Cho¹˙#, Sein Park¹˙#, Michael P. Gotsbacher², Peter Karuso², Ho Jeong Kwon¹˙*

¹Chemical Genomics Global Research Laboratory, Department of Biotechnology, College of Life Science &

Biotechnology, Yonsei University, Seoul 120-749, Korea, ²Department of Molecular Science, Macquarie University,
Sydney NSW 2109, Australia

Drug repositioning saves the time and cost of drug development in difficulties of FDA approval. It is a promising

approach reducing risk of side effects because it utilizes approved drugs. In this study, reverse chemical proteomics
was applied for access to new targets and pathways of existing drugs targeting anti-infectious diseases. Two case

compounds of Artesunate (ART) and Daptomycin (DAP) were investigated in this study. Both ART and DAP are the
most potent and safe antimalarial and antibacterial drugs, respectively. Despite their clinical potential, no human

target for them are known. The unbiased interrogation of several human cDNA libraries, displayed on bacteriophage
T7, revealed a high affinity human target of them; the Bcl-2 antagonist of cell death promoter (BAD) and ribosomal

protein S19 (RPS19), respectively. ART inhibits the phosphorylation of BAD, promoting the subsequent intrinsic
apoptosis. In addition, DAP exhibits selective growth inhibition of cell lines, particularly MCF7 and HUVECs. This

ability of DAP is due to regulate the expression of cell growth related cytokines, resulting in suppressed tumour
invasion. Collectively, these two case studies of reverse chemical proteomics demonstrate the potential of drug

repositioning of antibiotics to anticancer drug