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

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

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: rlaufer@uhnresearch.ca.
  • 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: hpauls@uhnresearch.ca.
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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-123675
    TTK Inhibitor