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 in cultured cells.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIABC010681-09
Application #
8763175
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
9
Fiscal Year
2013
Total Cost
$324,842
Indirect Cost
Name
National Cancer Institute Division of Basic Sciences
Department
Type
DUNS #
City
State
Country
Zip Code
Qian, Wen-Jian; Park, Jung-Eun; Grant, Robert et al. (2015) Neighbor-directed histidine N (Ï„)-alkylation: A route to imidazolium-containing phosphopeptide macrocycles. Biopolymers 104:663-73
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
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
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 36:858-77
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
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
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, Wen-Jian; Park, Jung-Eun; Lim, Dan et al. (2013) Peptide-based inhibitors of Plk1 polo-box domain containing mono-anionic phosphothreonine esters and their pivaloyloxymethyl prodrugs. Chem Biol 20:1255-64
He, Long; Lee, Junwon; Jang, Jae Hyuk et al. (2013) Osteoporosis regulation by salubrinal through eIF2α mediated differentiation of osteoclast and osteoblast. Cell Signal 25:552-60

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