Polo-Like Kinase Polo Box: Lead Target for Cancer Therapeutics

Summary Elevated expression of mammalian polo-like kinase (Plk) 1 occurs in many different types of cancers, such as head and neck, squamous cell carcinomas, oropharyngeal carcinomas, non-small cell lung cancer, melanomas, and ovarian and endometrial carcinomas. Plk1 has also been proposed as a novel diagnostic marker for several tumors. Polo kinases affect diverse cellular events during M-phase, such as centrosome maturation and bipolar spindle formation. Polo kinases also affect steps in the transition from G2 to M phase, such as activation of Cdc phosphatase activity, checkpoint adaptation, and the anaphase-promoting complex. Researchers at Harvard University have identified a domain in Polo-like kinase, the so-called polo box that is essential for mitosis and cell morphology. Overexpression of this domain regulates the kinase activity of Plk through intramolecular binding resulting, resulting in mitotic arrest. Thus, the generation of peptides of the polo-box domain for inhibition of Plk represents a lead agent for treatment of Plk-associated cancers.

Invention: A novel domain of polo-like kinase, the so called polo-box domain. The polo box domain regulates the kinase activity of Plk through intramolecular binding. In addition, the expression of the polo-box domain in vivo is correctly localized to the centrosome and blocks progression through mitosis. These data demonstrate that the polo-box domain of Plk has a critical role both in the regulation of its protein kinase activity and in localization of the enzyme, which influences progression through mitosis. The researchers also found that Plk1 depletion dramatically inhibited cell proliferation, decreased viability, and resulted in cell-cycle arrest with 4 N DNA content. Hence, these discoveries pave the way for the generation of therapeutic peptides for the treatment of Plk-associated cancers.

Applications Applications: The polo-box domain of Plk represents a lead target for the development of peptide therapeutics for the treatment of cell-cycle related cancers, such as lung, breast, uterus, ovary, cervix, epithelium, brain, retina, prostate, and throat. The polo-box domain of Plk also represents a lead target for the development of peptide therapeutics for fungal infections.

Publications Lee KS, Song S, Erikson RL. The polo-box-dependent induction of ectopic septal structures by a mammalian polo kinase, Plk, in Saccharomyces cerevisiae. Proc Natl Acad Sci U S A. 1999 Dec 7; 96(25):14360-5.

Lee KS, Grenfell TZ, Yarm FR, Erikson RL. Mutation of the polo-box disrupts localization and mitotic functions of the mammalian polo kinase Plk. Proc Natl Acad Sci U S A. 1998 Aug 4;95(16):9301

US Patent 6,358,738 For Further Information Please Contact the Director of Business Development Laura Brass Email: [email protected] Telephone: (617) 495-3067

Inventor(s): Erikson, Raymond Leo

Type of Offer: Licensing



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