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ID: ALA3352261

Journal: Bioorg Med Chem

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

Authors: Laufer R, Ng G, Liu Y, Patel NK, Edwards LG, Lang Y, Li SW, Feher M, Awrey DE, Leung G, Beletskaya I, Plotnikova O, Mason JM, Hodgson R, Wei X, Mao G, Luo X, Huang P, Green E, Kiarash R, Lin DC, Harris-Brandts M, Ban F, Nadeem V, Mak TW, Pan GJ, Qiu W, Chirgadze NY, Pauls HW.

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.

CiteXplore: 25043312

DOI: 10.1016/j.bmc.2014.06.027