Journal
BIOORGANIC & MEDICINAL CHEMISTRY
Volume 22, Issue 17, Pages 4968-4997Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2014.06.027
Keywords
Anticancer, antimitotic agents; Indazolyl benzenesulfonamide; Mitotic kinase; Monopolar Spindle 1 kinase (Mps1); Tyrosine Threonine Kinase (TTK)
Funding
- Princess Margaret Cancer Foundation
- Canadian Institute of Health Research
- Canadian Foundation for Innovation
- U. S. Department of Energy, Office of Science, Office of Basic Energy Sciences [W-31-109-Eng-38]
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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 = 3.6 nM) 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. (C) 2014 Elsevier Ltd. All rights reserved.
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