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Targeting Polo-like Kinase 1 In Cancer Therapy | 8280
ISSN: 0975-0851

Journal of Bioequivalence & Bioavailability
Open Access

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Targeting polo-like kinase 1 in cancer therapy

International Conference and Exhibiton on Pharmaceutical Regulatory Affairs

Kyung Lee

Keynote: JBB

DOI: 10.4172/0975-0851.1000106

Development of mono-specifi c anti-cancer therapeutics against important protein ki- nase targets has long been sought by pharmaceutical and academic laboratories. Until now, the current prevailing strategy of inhibiting the catalytic activity of the kinases has suff ered from a high level of cross-reactivity with other unrelated kinases. Protein-protein interac- tion inhibitors are thought to be highly specifi c and, therefore, more amenable for com- binatorial therapy with less toxicological problems. However, largely due to the diffi culty of fi nding a right target with a small, well-defi ned, and unique binding cleft has hampered the development of this class of therapeutic agents. Recently, polo-like kinase 1 (Plk1) has been singled out as the only kinase essentially required for the viability of activated Ras or inactivated p53 mutation-bearing cancer cells, but not the respective normal cells. Consistently, Plk1 overexpression has shown to be tightly associated with poor prognosis for various types of cancers in humans. Th us, Plk1 is undoubtedly one of the most at- tractive anti-cancer drug targets. We have identifi ed a minimal peptide, PLHSpT, which specifi cally binds to the non-catalytic polo-box domain (PBD) of Plk1 with an unusually high affi nity. Inhibition of the PBD function was suffi cient to kill cancer cells of diverse origins, but not the respective normal cells. In line with this observation, provision of a novel, non-hydrolysable, phospho-Th r mimetic peptide, PLHS-Pmab, induced mitotic ar- rest and apoptosis in cancer cells by disrupting the function of Plk1. Currently, we employ both structure-based drug design and novel chemical synthesis methods to generate mono- specifi c anti-Plk1 therapeutic agent. We use the PLHS-Pmab mimetic peptide as a template and covalently conjugate it with rationally designed chemical moieties to further enhance its binding affi nity to the PBD. Th is work involves both innovative design and synthesis of a wide spectrum of chemical moieties to achieve site-specifi c chemical properties with distinct biological activities. We believe that this study may likely lead to the generation of a new class of mono-specifi c anti-Plk1 therapeutic agent that could facilitate a broad range of anti-cancer therapy.
Dr. Kyung Lee received his Ph.D. in 1994 from the Department of Biochemistry at the Johns Hopkins University in Baltimore. He then worked with Raymond Erikson at Harvard University as a postdoctoral fellow and studied in the fi elds of cellular proliferation and mitotic controls. In 1998, he joined National Institutes of Health as a tenure-track investigator in the Laboratory of Metabolism at National Cancer Institute. In 2005, Dr. Lee became a senior investigator and head of the Chemistry Section, Laboratory of Metabolism