Page 15 - I. Chemical biology and drug discovery

Identification of unanticipated human targets of antibiotics
Artesunate for anti-cancer drug repositioning.

Sung Min Cho , Sein Park , Michael P. Gotsbacher , Peter Karuso and Ho Jeong Kwon 1,*
1
2
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1 Chemical Genomics Global Research Laboratory, Department of Biotechnology, College of Life Science & Biotechnology, Yonsei University, 50 Yonsei-ro,
2
Seodaemun-gu, Seoul 120-749, Korea, Department of Molecular Sciences, Macquarie University, Sydney, NSW 2109, Australia * Corresponding author:
kwonhj@yonsei.ac.kr
BACKGROUND AIM
▶ Drug repositioning? ART is the most potent and safe antimalarial and antibacterial drug.
- Simple process to develop new approved drugs Despite its clinical potential, no human target for ART are known.
- Less time and cost In this study, unbiased interrogation of several human cDNA
-Tigecyclin (Tygacil): From Antibiotic for S. libraries, displayed on bacteriophage T7, was applied to reveal a
aureus to Anti-cancer drug for Acute myeloid
leukemia. high affinity human target of them.
- Salinomycin: From Antibiotic for Methicillin-
resistant staphylococcus aureus to Anti-cancer
drug for Breast cancer stem cell.
METHODS

▶ Phage display is a powerful method for
identification of target proteins of a compound.
▶ Target proteins can be identified by an affinity
selection method called biopanning.
▶ To identify target proteins, cDNA is amplified ▶ A new technology for target identification of non-labeled small molecules.
by PCR and analyzed by DNA sequencing. ▶ Target protein bound with drug has high stability against pronase.
▶ This method is not only easy and quick to ▶ Pronase can not easily degrade drug-bound proteins.
identify target proteins, but also economically ▶ Proteins are detected by immunoblotting, and the difference of protein
useful. bands means the possibility of drug’s target.
RESULTS
Target identification using a phage display ART binds to S136 of BAD

Validation of ART’s target protein, BAD ART induces intrinsic apoptosis
Competition assay Colocalization of F-ART and BAD

DARTS assay
Synergic effect of ART and Camp for cancer therapy

Drug sensitivity assay with Small interfering RNA

CONCLUSION REFERENCES ACKNOWLEDGEMENTS

- Lomenick et al . Target identification using drug
▶ A unbiased, reverse chemical proteomics screen of Supported by grants from the National Research
ART binding protein in several human cancer cells affinity responsive target stability DARTS. Curr Protoc Foundation of Korea (MSIP; 2015K1A1A2028365,
identified BAD as biologically relevant target protein of Chem Biol. 2011 2015M3A9C4076321, 2016K2A9A1A03904900) and
ART in humans. Brain Korea 21 Plus Project, Republic of Korea.
- Shim et al., A New Curcumin Derivative, HBC,
▶ The BAD-ART interaction can also now be used in Interferes with the Cell Cycle Progression of Colon Contact information
rational drug design to produce even better and Cancer Cells via Antagonization of the
patentable anticancer drugs.
Ca2+/Calmodulin Function. Chemistry & Biology 2004
• Presenter : Sung Min Cho
sungmincho@yonsei.ac.kr
This study identified target proteins of antibiotic and provided - Michael P. Gotsbacher et al. Reverse Chemical
new target for developing this antibiotic to anti-cancer agent. Proteomics Identifies an Unanticipated Human Target • Correspondence : Ho Jeong Kwon
of the Antimalarial Artesunate. ACS Chem. Biol. 2019 kwonhj@yonsei.ac.kr