Abstract

Polo-like kinase 1 (Plk1) is one of the most attractive targets for anti-cancer therapy. Efforts to generate Plk1-specific inhibitors by targeting the catalytic activity of Plk1 have proven to be difficult due to similarities with the catalytic domains of other structurally related kinases. Here, we propose to develop a new class of mono-specific Plk1 inhibitors by employing a novel approach of targeting the non-catalytic, but functionally essential, PBD of Plk1. To this end, we have carried out a high throughput screen in collaboration with National Center for Advancing Translational Sciences (NCATS), Bethesda, MD. My NIH X01 grant proposal was approved for this particular project. From this screen, we have identified 3,000 compounds from a primary screen, which were narrowed down to the final 8 compounds through secondary medium throughput and tertiary cell-based assays. Currently, we are in the middle of further testing these compounds by using both in vitro biochemical assays and cell-based assays, and carrying out chemical modification of these compounds for improvement.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIABC010681-10
Application #
8937804
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
10
Fiscal Year
2014
Total Cost
Indirect Cost

  Institution

Name
Basic Sciences
Department
Type
DUNS #
City
State
Country
Zip Code

  Publications

Park, Jung-Eun; Hymel, David; Burke Jr, Terrence R et al. (2017) Current progress and future perspectives in the development of anti-polo-like kinase 1 therapeutic agents. F1000Res 6:1024
Lee, Kyung S; Burke Jr, Terrence R; Park, Jung-Eun et al. (2015) Recent Advances and New Strategies in Targeting Plk1 for Anticancer Therapy. Trends Pharmacol Sci 36:858-877
Kim, Ju Hee; Ku, Bonsu; Lee, Kyung S et al. (2015) Structural analysis of the polo-box domain of human Polo-like kinase 2. Proteins :
Jia, Jia-Lin; Han, Young-Hyun; Kim, Hak-Cheol et al. (2015) Structural basis for recognition of Emi2 by Polo-like kinase 1 and development of peptidomimetics blocking oocyte maturation and fertilization. Sci Rep 5:14626
Park, Jung-Eun; Kim, Tae-Sung; Kim, Bo Yeon et al. (2015) Selective blockade of cancer cell proliferation and anchorage-independent growth by Plk1 activity-dependent suicidal inhibition of its polo-box domain. Cell Cycle 14:3624-34
Qian, Wen-Jian; Park, Jung-Eun; Grant, Robert et al. (2015) Neighbor-directed histidine N (?)-alkylation: A route to imidazolium-containing phosphopeptide macrocycles. Biopolymers 104:663-73
Qian, Wen-Jian; Park, Jung-Eun; Lim, Dan et al. (2014) Mono-anionic phosphopeptides produced by unexpected histidine alkylation exhibit high Plk1 polo-box domain-binding affinities and enhanced antiproliferative effects in HeLa cells. Biopolymers 102:444-55
Srinivasrao, Ganipisetti; Park, Jung-Eun; Kim, Sungmin et al. (2014) Design and synthesis of a cell-permeable, drug-like small molecule inhibitor targeting the polo-box domain of polo-like kinase 1. PLoS One 9:e107432
Kim, Sun-Ok; Sakchaisri, Krisada; Thimmegowda, N R et al. (2013) STK295900, a dual inhibitor of topoisomerase 1 and 2, induces G(2) arrest in the absence of DNA damage. PLoS One 8:e53908
Qian, Wenjian; Park, Jung-Eun; Liu, Fa et al. (2013) Effects on polo-like kinase 1 polo-box domain binding affinities of peptides incurred by structural variation at the phosphoamino acid position. Bioorg Med Chem 21:3996-4003

Showing the most recent 10 out of 18 publications