2. Academic Validation
  3. The discovery of PLK4 inhibitors: (E)-3-((1H-Indazol-6-yl)methylene)indolin-2-ones as novel antiproliferative agents

The discovery of PLK4 inhibitors: (E)-3-((1H-Indazol-6-yl)methylene)indolin-2-ones as novel antiproliferative agents

  • J Med Chem. 2013 Aug 8;56(15):6069-87. doi: 10.1021/jm400380m.
Radoslaw Laufer 1,  Bryan Forrest,  Sze-Wan Li,  Yong Liu,  Peter Sampson,  Louise Edwards,  Yunhui Lang,  Donald E Awrey,  Guodong Mao,  Olga Plotnikova,  Genie Leung,  Richard Hodgson,  Irina Beletskaya,  Jacqueline M Mason,  Xunyi Luo,  Xin Wei,  Yi Yao,  Miklos Feher,  Fuqiang Ban,  Reza Kiarash,  Erin Green,  Tak W Mak,  Guohua Pan,  Henry W Pauls
Affiliations

Affiliation

  • 1 Campbell Family Institute for Breast Cancer Research, TMDT East Tower, MaRS Centre, 101 College Street, Toronto, Ontario MG5 1L7, Canada.
PMID: 23829549 DOI: 10.1021/jm400380m
Abstract

The family of Polo-like kinases is important in the regulation of mitotic progression; this work keys on one member, namely Polo-like kinase 4 (PLK4). PLK4 has been identified as a candidate Anticancer target which prompted a search for potent and selective inhibitors of PLK4. The body of the paper describes lead generation and optimization work which yielded nanomolar PLK4 inhibitors. Lead generation began with directed virtual screening, using a ligand-based focused library and a PLK4 homology model. Validated hits were used as starting points for the design and discovery of PLK4 inhibitors of novel structure, namely (E)-3-((1H-indazol-6-yl)methylene)indolin-2-ones. Computational models, based on a published X-ray structure (PLK4 kinase domain), were used to understand and optimize the in vitro activity of the series; potent antiproliferative activity was obtained. The kinase selectivity profile and cell cycle analysis of selected inhibitors are described. The results of a xenograft study with an optimized compound 50 (designated CFI-400437) support the potential of these novel PLK4 inhibitors for Cancer therapy.

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