title: Discovery of inhibitors of the mitotic kinase TTK based on N-(3-(3-sulfamoylphenyl)-1H-indazol-5-yl)-acetamides and carboxamides.
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.
authors.affiliation: Campbell Family Institute for Breast Cancer Research, Therapeutics Group, University Health Network, 101 College St. W, Toronto, Ontario M5G 1L7, Canada. Electronic address: rlaufer@uhnresearch.ca.
authors.forename: Radoslaw
authors.initials: R
authors.lastname: Laufer
authors.affiliation: Campbell Family Institute for Breast Cancer Research, Therapeutics Group, University Health Network, 101 College St. W, Toronto, Ontario M5G 1L7, Canada.
authors.forename: Grace
authors.initials: G
authors.lastname: Ng
authors.affiliation: Campbell Family Institute for Breast Cancer Research, Therapeutics Group, University Health Network, 101 College St. W, Toronto, Ontario M5G 1L7, Canada.
authors.forename: Yong
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Campbell Family Institute for Breast Cancer Research, Therapeutics Group, University Health Network, 101 College St. W, Toronto, Ontario M5G 1L7, Canada.
authors.forename: Narendra Kumar B
authors.initials: NK
authors.lastname: Patel
authors.affiliation: Campbell Family Institute for Breast Cancer Research, Therapeutics Group, University Health Network, 101 College St. W, Toronto, Ontario M5G 1L7, Canada.
authors.forename: Louise G
authors.initials: LG
authors.lastname: Edwards
authors.affiliation: Campbell Family Institute for Breast Cancer Research, Therapeutics Group, University Health Network, 101 College St. W, Toronto, Ontario M5G 1L7, Canada.
authors.forename: Yunhui
authors.initials: Y
authors.lastname: Lang
authors.affiliation: Campbell Family Institute for Breast Cancer Research, Therapeutics Group, University Health Network, 101 College St. W, Toronto, Ontario M5G 1L7, Canada.
authors.forename: Sze-Wan
authors.initials: SW
authors.lastname: Li
authors.affiliation: Campbell Family Institute for Breast Cancer Research, Therapeutics Group, University Health Network, 101 College St. W, Toronto, Ontario M5G 1L7, Canada.
authors.forename: Miklos
authors.initials: M
authors.lastname: Feher
authors.affiliation: Campbell Family Institute for Breast Cancer Research, Therapeutics Group, University Health Network, 101 College St. W, Toronto, Ontario M5G 1L7, Canada.
authors.forename: Don E
authors.initials: DE
authors.lastname: Awrey
authors.affiliation: Campbell Family Institute for Breast Cancer Research, Therapeutics Group, University Health Network, 101 College St. W, Toronto, Ontario M5G 1L7, Canada.
authors.forename: Genie
authors.initials: G
authors.lastname: Leung
authors.affiliation: Campbell Family Institute for Breast Cancer Research, Therapeutics Group, University Health Network, 101 College St. W, Toronto, Ontario M5G 1L7, Canada.
authors.forename: Irina
authors.initials: I
authors.lastname: Beletskaya
authors.affiliation: Campbell Family Institute for Breast Cancer Research, Therapeutics Group, University Health Network, 101 College St. W, Toronto, Ontario M5G 1L7, Canada.
authors.forename: Olga
authors.initials: O
authors.lastname: Plotnikova
authors.affiliation: Campbell Family Institute for Breast Cancer Research, Therapeutics Group, University Health Network, 101 College St. W, Toronto, Ontario M5G 1L7, Canada.
authors.forename: Jacqueline M
authors.initials: JM
authors.lastname: Mason
authors.affiliation: Campbell Family Institute for Breast Cancer Research, Therapeutics Group, University Health Network, 101 College St. W, Toronto, Ontario M5G 1L7, Canada.
authors.forename: Richard
authors.initials: R
authors.lastname: Hodgson
authors.affiliation: Campbell Family Institute for Breast Cancer Research, Therapeutics Group, University Health Network, 101 College St. W, Toronto, Ontario M5G 1L7, Canada.
authors.forename: Xin
authors.initials: X
authors.lastname: Wei
authors.affiliation: Campbell Family Institute for Breast Cancer Research, Therapeutics Group, University Health Network, 101 College St. W, Toronto, Ontario M5G 1L7, Canada.
authors.forename: Guodong
authors.initials: G
authors.lastname: Mao
authors.affiliation: Campbell Family Institute for Breast Cancer Research, Therapeutics Group, University Health Network, 101 College St. W, Toronto, Ontario M5G 1L7, Canada.
authors.forename: Xunyi
authors.initials: X
authors.lastname: Luo
authors.affiliation: Campbell Family Institute for Breast Cancer Research, Therapeutics Group, University Health Network, 101 College St. W, Toronto, Ontario M5G 1L7, Canada.
authors.forename: Ping
authors.initials: P
authors.lastname: Huang
authors.affiliation: Campbell Family Institute for Breast Cancer Research, Therapeutics Group, University Health Network, 101 College St. W, Toronto, Ontario M5G 1L7, Canada.
authors.forename: Erin
authors.initials: E
authors.lastname: Green
authors.affiliation: Campbell Family Institute for Breast Cancer Research, Therapeutics Group, University Health Network, 101 College St. W, Toronto, Ontario M5G 1L7, Canada; Campbell Family Cancer Research Institute, Ontario Cancer Institute, Princess Margaret Hospital, University Health Network, 610 University Ave, Toronto, Ontario M5G 2C4, Canada.
authors.forename: Reza
authors.initials: R
authors.lastname: Kiarash
authors.affiliation: Campbell Family Institute for Breast Cancer Research, Therapeutics Group, University Health Network, 101 College St. W, Toronto, Ontario M5G 1L7, Canada.
authors.forename: Dan Chi-Chia
authors.initials: DC
authors.lastname: Lin
authors.affiliation: Campbell Family Institute for Breast Cancer Research, Therapeutics Group, University Health Network, 101 College St. W, Toronto, Ontario M5G 1L7, Canada.
authors.forename: Marees
authors.initials: M
authors.lastname: Harris-Brandts
authors.affiliation: Campbell Family Institute for Breast Cancer Research, Therapeutics Group, University Health Network, 101 College St. W, Toronto, Ontario M5G 1L7, Canada.
authors.forename: Fuqiang
authors.initials: F
authors.lastname: Ban
authors.affiliation: Campbell Family Institute for Breast Cancer Research, Therapeutics Group, University Health Network, 101 College St. W, Toronto, Ontario M5G 1L7, Canada.
authors.forename: Vincent
authors.initials: V
authors.lastname: Nadeem
authors.affiliation: Campbell Family Institute for Breast Cancer Research, Therapeutics Group, University Health Network, 101 College St. W, Toronto, Ontario M5G 1L7, Canada.
authors.forename: Tak W
authors.initials: TW
authors.lastname: Mak
authors.affiliation: Campbell Family Institute for Breast Cancer Research, Therapeutics Group, University Health Network, 101 College St. W, Toronto, Ontario M5G 1L7, Canada.
authors.forename: Guohua J
authors.initials: GJ
authors.lastname: Pan
authors.affiliation: Campbell Family Cancer Research Institute, Ontario Cancer Institute, Princess Margaret Hospital, University Health Network, 610 University Ave, Toronto, Ontario M5G 2C4, Canada.
authors.forename: Wei
authors.initials: W
authors.lastname: Qiu
authors.affiliation: Campbell Family Cancer Research Institute, Ontario Cancer Institute, Princess Margaret Hospital, University Health Network, 610 University Ave, Toronto, Ontario M5G 2C4, Canada.
authors.forename: Nickolay Y
authors.initials: NY
authors.lastname: Chirgadze
authors.affiliation: Campbell Family Institute for Breast Cancer Research, Therapeutics Group, University Health Network, 101 College St. W, Toronto, Ontario M5G 1L7, Canada. Electronic address: hpauls@uhnresearch.ca.
authors.forename: Henry W
authors.initials: HW
authors.lastname: Pauls
mesh_terms: D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D044482:Benzeneacetamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D006801:Humans; D007191:Indazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: C000596490:2-(dimethylamino)-2-(2-ethylphenyl)-N-(3-(3-sulfamoylphenyl)-1H-indazol-5-yl)acetamide; D000577:Amides; D044482:Benzeneacetamides; D018797:Cell Cycle Proteins; D007191:Indazoles; D047428:Protein Kinase Inhibitors; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; C075840:TTK protein, human
keywords: Anticancer; Indazolyl benzenesulfonamide; Mitotic kinase; Monopolar Spindle 1 kinase (Mps1); Tyrosine Threonine Kinase (TTK); antimitotic agents