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Bioorg Med Chem. 2014 Sep 1;22(17):4968-97. doi: 10.1016/j.bmc.2014.06.027. Epub 2014 Jun 23.

Discovery of inhibitors of the mitotic kinase TTK based on N-(3-(3-sulfamoylphenyl)-1H-indazol-5-yl)-acetamides and carboxamides.

Author information

  • 1Campbell Family Institute for Breast Cancer Research, Therapeutics Group, University Health Network, 101 College St. W, Toronto, Ontario M5G 1L7, Canada. Electronic address: rlaufer@uhnresearch.ca.
  • 2Campbell Family Institute for Breast Cancer Research, Therapeutics Group, University Health Network, 101 College St. W, Toronto, Ontario M5G 1L7, Canada.
  • 3Campbell Family Institute for Breast Cancer Research, Therapeutics Group, University Health Network, 101 College St. W, Toronto, Ontario M5G 1L7, Canada; Campbell Family Cancer Research Institute, Ontario Cancer Institute, Princess Margaret Hospital, University Health Network, 610 University Ave, Toronto, Ontario M5G 2C4, Canada.
  • 4Campbell Family Cancer Research Institute, Ontario Cancer Institute, Princess Margaret Hospital, University Health Network, 610 University Ave, Toronto, Ontario M5G 2C4, Canada.
  • 5Campbell Family Institute for Breast Cancer Research, Therapeutics Group, University Health Network, 101 College St. W, Toronto, Ontario M5G 1L7, Canada. Electronic address: hpauls@uhnresearch.ca.

Abstract

TTK kinase was identified by in-house siRNA screen and pursued as a tractable, novel target for cancer treatment. A screening campaign and systematic optimization, supported by computer modeling led to an indazole core with key sulfamoylphenyl and acetamido moieties at positions 3 and 5, respectively, establishing a novel chemical class culminating in identification of 72 (CFI-400936). This potent inhibitor of TTK (IC50=3.6nM) demonstrated good activity in cell based assay and selectivity against a panel of human kinases. A co-complex TTK X-ray crystal structure and results of a xenograft study with TTK inhibitors from this class are described.

Copyright © 2014 Elsevier Ltd. All rights reserved.

KEYWORDS:

Anticancer; Indazolyl benzenesulfonamide; Mitotic kinase; Monopolar Spindle 1 kinase (Mps1); Tyrosine Threonine Kinase (TTK); antimitotic agents

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