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

doi:10.1016/j.bmc.2014.06.027

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

Bioorg Med Chem. 2014 Sep 1;22(17):4968-97. doi: 10.1016/j.bmc.2014.06.027. Epub 2014 Jun 23.

Authors

Radoslaw Laufer¹, Grace Ng², Yong Liu², Narendra Kumar B Patel², Louise G Edwards², Yunhui Lang², Sze-Wan Li², Miklos Feher², Don E Awrey², Genie Leung², Irina Beletskaya², Olga Plotnikova², Jacqueline M Mason², Richard Hodgson², Xin Wei², Guodong Mao², Xunyi Luo², Ping Huang², Erin Green², Reza Kiarash³, Dan Chi-Chia Lin², Marees Harris-Brandts², Fuqiang Ban², Vincent Nadeem², Tak W Mak², Guohua J Pan², Wei Qiu⁴, Nickolay Y Chirgadze⁴, Henry W Pauls⁵

Affiliations

¹ 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.
² Campbell Family Institute for Breast Cancer Research, Therapeutics Group, University Health Network, 101 College St. W, Toronto, Ontario M5G 1L7, Canada.
³ 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.
⁴ Campbell Family Cancer Research Institute, Ontario Cancer Institute, Princess Margaret Hospital, University Health Network, 610 University Ave, Toronto, Ontario M5G 2C4, Canada.
⁵ 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.

PMID: 25043312
DOI: 10.1016/j.bmc.2014.06.027

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.

Keywords: Anticancer; Indazolyl benzenesulfonamide; Mitotic kinase; Monopolar Spindle 1 kinase (Mps1); Tyrosine Threonine Kinase (TTK); antimitotic agents.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amides / chemical synthesis
Amides / chemistry
Amides / pharmacology*
Benzeneacetamides / chemical synthesis
Benzeneacetamides / chemistry
Benzeneacetamides / pharmacology*
Cell Cycle Proteins / antagonists & inhibitors*
Cell Cycle Proteins / metabolism
Crystallography, X-Ray
Dose-Response Relationship, Drug
Drug Discovery*
Humans
Indazoles / chemical synthesis
Indazoles / chemistry
Indazoles / pharmacology*
Models, Molecular
Molecular Structure
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Protein Serine-Threonine Kinases / antagonists & inhibitors*
Protein Serine-Threonine Kinases / metabolism
Protein-Tyrosine Kinases / antagonists & inhibitors*
Protein-Tyrosine Kinases / metabolism
Structure-Activity Relationship

Substances

2-(dimethylamino)-2-(2-ethylphenyl)-N-(3-(3-sulfamoylphenyl)-1H-indazol-5-yl)acetamide
Amides
Benzeneacetamides
Cell Cycle Proteins
Indazoles
Protein Kinase Inhibitors
Protein-Tyrosine Kinases
Protein Serine-Threonine Kinases
TTK protein, human