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Ref Type Journal Article
PMID (25043312)
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
Vol 22
Issue 17
Date 2014 Sep 1
URL
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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
CFI-400936 CFI-400936 1 0
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