Development of a Polo-like Kinase-1 Polo-Box Domain Inhibitor as a Tumor Growth Suppressor in Mice Models

  • J Med Chem. 2020 Dec 10;63(23):14905-14920. doi: 10.1021/acs.jmedchem.0c01451.
Pethaiah Gunasekaran  1 ,  Min Su Yim  1  2 ,  Mija Ahn  1 ,  Nak-Kyun Soung  3 ,  Jung-Eun Park  4 ,  Jaehi Kim  1 ,  Geul Bang  5 ,  Sang Chul Shin  6 ,  Joonhyeok Choi  1 ,  Minkyoung Kim  7 ,  Hak Nam Kim  1 ,  Young-Ho Lee  1  2 ,  Young-Ho Chung  8 ,  Kyeong Lee  7 ,  Eunice EunKyeong Kim  6 ,  Young-Ho Jeon  9 ,  Min Ju Kim  10 ,  Kyeong-Ryoon Lee  10 ,  Bo-Yeon Kim  3 ,  Kyung S Lee  4 ,  Eun Kyoung Ryu  1  2 ,  Jeong Kyu Bang  1  2
Affiliations
  • 1. Division of Magnetic Resonance, Korea Basic Science Institute (KBSI), Ochang, Chung Buk 28119, Republic of Korea.
  • 2. Department of Bio-analytical Science, University of Science & Technology, Daejeon 34113, Republic of Korea.
  • 3. Anticancer Agent Research Center, Korea Research Institute of Bioscience and Biotechnology, 30 Yeongudanji-ro, Ochang, Cheongwon, Chungbuk 28116, Republic of Korea.
  • 4. Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892, United States.
  • 5. Biomedical Omics Group, Korea Basic Science Institute, Ochang, Chung-Buk 363-883, Republic of Korea.
  • 6. Biomedical Research Institute, Korea Institute of Science and Technology, Hwarangno 14-gil 5, Seongbuk-gu, Seoul 02792, Republic of Korea.
  • 7. College of Pharmacy, Dongguk University, 52 Dongguk-ro, Ilsandong-gu, Goyang 10320, Republic of Korea.
  • 8. Drug & Disease Target Research Team, Korea Basic Science Institute (KBSI), Ochang, Chung Buk 28119, Republic of Korea.
  • 9. Laboratory of Biochemistry and Structural Biology, College of Pharmacy, Korea University, Sejong 30019, Republic of Korea.
  • 10. Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology, 30 Yeongudanji-ro, Ochang, Cheongwon, Chungbuk 28116, Republic of Korea.
PMID: 33142063 DOI: 10.1021/acs.jmedchem.0c01451
Abstract

Polo-like kinase-1 (PLK1) plays a key role in Mitosis and has been identified as an attractive Anticancer drug target. PLK1 consists of two drug-targeting sites, namely, N-terminal kinase domain (KD) and C-terminal polo-box domain (PBD). As KD-targeting inhibitors are associated with severe side effects, here we report on the pyrazole-based PLK1 PBD inhibitor, KBJK557, which showed a remarkable in vitro Anticancer effect by inducing PLK1 delocalization, mitotic arrest, and Apoptosis in HeLa cells. Further, in vivo optical imaging analysis and antitumorigenic activities in mouse xenograft models demonstrate that KBJK557 preferentially accumulates in Cancer cells and selectively inhibits Cancer cell proliferation. Pharmacokinetic profiles and partition coefficients suggest that KBJK557 was exposed in the blood and circulated through the organs with an intermediate level of clearance (t1/2, 7.73 h). The present investigation offers a strategy for specifically targeting Cancer using a newly identified small-molecule inhibitor that targets the PLK1 PBD.

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