Bioorganic & Medicinal Chemistry 2014-09-01

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

Radoslaw Laufer, Grace Ng, Yong Liu, Narendra Kumar B Patel, Louise G Edwards, Yunhui Lang, Sze-Wan Li, Miklos Feher, Don E Awrey, Genie Leung, Irina Beletskaya, Olga Plotnikova, Jacqueline M Mason, Richard Hodgson, Xin Wei, Guodong Mao, Xunyi Luo, Ping Huang, Erin Green, Reza Kiarash, Dan Chi-Chia Lin, Marees Harris-Brandts, Fuqiang Ban, Vincent Nadeem, Tak W Mak, Guohua J Pan, Wei Qiu, Nickolay Y Chirgadze, Henry W Pauls

Index: Bioorg. Med. Chem. 22(17) , 4968-97, (2014)

Full Text: HTML

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.