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Discovery of inhibitors of the mitotic kinase TTK based on N-(3-(3-sulfamoylphenyl)-1H-indazol-5-yl)-acetamides and carboxamides.
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
Sep 01 2014
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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.