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

  • Bioorg Med Chem. 2014 Sep 1;22(17):4968-97. doi: 10.1016/j.bmc.2014.06.027.
Radoslaw Laufer  1 ,  Grace Ng  2 ,  Yong Liu  2 ,  Narendra Kumar B Patel  2 ,  Louise G Edwards  2 ,  Yunhui Lang  2 ,  Sze-Wan Li  2 ,  Miklos Feher  2 ,  Don E Awrey  2 ,  Genie Leung  2 ,  Irina Beletskaya  2 ,  Olga Plotnikova  2 ,  Jacqueline M Mason  2 ,  Richard Hodgson  2 ,  Xin Wei  2 ,  Guodong Mao  2 ,  Xunyi Luo  2 ,  Ping Huang  2 ,  Erin Green  2 ,  Reza Kiarash  3 ,  Dan Chi-Chia Lin  2 ,  Marees Harris-Brandts  2 ,  Fuqiang Ban  2 ,  Vincent Nadeem  2 ,  Tak W Mak  2 ,  Guohua J Pan  2 ,  Wei Qiu  4 ,  Nickolay Y Chirgadze  4 ,  Henry W Pauls  5
Affiliations
  • 1. Campbell Family Institute for Breast Cancer Research, Therapeutics Group, University Health Network, 101 College St. W, Toronto, Ontario M5G 1L7, Canada. Electronic address: [email protected].
  • 2. Campbell Family Institute for Breast Cancer Research, Therapeutics Group, University Health Network, 101 College St. W, Toronto, Ontario M5G 1L7, Canada.
  • 3. Campbell 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.
  • 4. Campbell Family Cancer Research Institute, Ontario Cancer Institute, Princess Margaret Hospital, University Health Network, 610 University Ave, Toronto, Ontario M5G 2C4, Canada.
  • 5. Campbell Family Institute for Breast Cancer Research, Therapeutics Group, University Health Network, 101 College St. W, Toronto, Ontario M5G 1L7, Canada. Electronic address: [email protected].
PMID: 25043312 DOI: 10.1016/j.bmc.2014.06.027
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.

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