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|Ref Type||Journal Article|
|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|
|Title||Discovery of inhibitors of the mitotic kinase TTK based on N-(3-(3-sulfamoylphenyl)-1H-indazol-5-yl)-acetamides and carboxamides.|
|Journal||Bioorganic & medicinal chemistry|
|Date||2014 Sep 1|
|Abstract Text||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.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|CFI-400936||MPS1 Inhibitor 25||CFI-400936 is an inhibitor of TTK (MPS1), which inhibits cell proliferation (PMID: 25043312).|
|Reversine||AURK Inhibitor (Pan) 11 MPS1 Inhibitor 25||Reversine is an A3 adenosine receptor antagonist and pan-Aurora kinase and TTK (MPS1) inhibitor, which prevents cell proliferation (PMID: 14719906, PMID: 18483302, PMID: 25043312).|
|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|Unknown unknown||colon cancer||not applicable||CFI-400936||Preclinical - Cell line xenograft||Actionable||In a preclinical study, CFI-400936 inhibited tumor growth in a human cell line xenograft model of colon cancer (PMID: 25043312).||25043312|