title: Discovery of 4-(4-aminopyrazolo[1,5-a][1,3,5]triazin-8-yl)benzamides as novel, highly potent and selective, orally bioavailable inhibitors of Tyrosine Threonine Kinase, TTK.
abstract: TTK/Mps1 is a key kinase controlling progression of cell division via participation in the mitotic spindle assembly checkpoint and is overexpressed in a number of human cancers. Herein we report the discovery of 4-(4-aminopyrazolo[1,5-a][1,3,5]triazin-8-yl)benzamides as a potent, novel class of TTK inhibitors. The series was identified by means of bioisosteric replacement of the related imidazopyrazine and imidazopyridazine scaffolds. Optimization led to the identification of compounds with excellent potency (Ki=0.8nM) and exceptional kinase selectivity. The SAR indicates a strong dependence of activity on the presence of the N-cyclopropyl-2-methylbenzamide moiety delineating the geometry for 1½ type kinase inhibitor. Molecular modeling indicates the extensive and optimal contacts, mediated through H-bonds and hydrophobic interactions, are responsible for the selectivity and potency of the inhibitors. The compounds demonstrate a strong anti-proliferative activity in a panel of human cancer cell lines (HCT116 GI50<15nM) and good rodent pharmacokinetics (oral %F 97%).
authors.affiliation: Campbell Family Institute for Breast Cancer Research, University Health Network, TMDT East Tower, MaRS Centre, 101 College Street, Toronto, Ontario M5G 1L7, Canada. Electronic address: Radek.Laufer@oicr.on.ca.
authors.forename: Radoslaw
authors.initials: R
authors.lastname: Laufer
authors.affiliation: Campbell Family Institute for Breast Cancer Research, University Health Network, TMDT East Tower, MaRS Centre, 101 College Street, Toronto, Ontario M5G 1L7, Canada.
authors.forename: Sze-Wan
authors.initials: SW
authors.lastname: Li
authors.affiliation: Campbell Family Institute for Breast Cancer Research, University Health Network, TMDT East Tower, MaRS Centre, 101 College Street, Toronto, Ontario M5G 1L7, Canada.
authors.forename: Yong
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Campbell Family Institute for Breast Cancer Research, University Health Network, TMDT East Tower, MaRS Centre, 101 College Street, Toronto, Ontario M5G 1L7, Canada.
authors.forename: Grace
authors.initials: G
authors.lastname: Ng
authors.affiliation: Campbell Family Institute for Breast Cancer Research, University Health Network, TMDT East Tower, MaRS Centre, 101 College Street, Toronto, Ontario M5G 1L7, Canada.
authors.forename: Yunhui
authors.initials: Y
authors.lastname: Lang
authors.affiliation: Campbell Family Institute for Breast Cancer Research, University Health Network, TMDT East Tower, MaRS Centre, 101 College Street, Toronto, Ontario M5G 1L7, Canada.
authors.forename: Miklos
authors.initials: M
authors.lastname: Feher
authors.affiliation: Campbell Family Institute for Breast Cancer Research, University Health Network, TMDT East Tower, MaRS Centre, 101 College Street, Toronto, Ontario M5G 1L7, Canada.
authors.forename: Richard
authors.initials: R
authors.lastname: Brokx
authors.affiliation: Campbell Family Institute for Breast Cancer Research, University Health Network, TMDT East Tower, MaRS Centre, 101 College Street, Toronto, Ontario M5G 1L7, Canada.
authors.forename: Irina
authors.initials: I
authors.lastname: Beletskaya
authors.affiliation: Campbell Family Institute for Breast Cancer Research, University Health Network, TMDT East Tower, MaRS Centre, 101 College Street, Toronto, Ontario M5G 1L7, Canada.
authors.forename: Richard
authors.initials: R
authors.lastname: Hodgson
authors.affiliation: Campbell Family Institute for Breast Cancer Research, University Health Network, TMDT East Tower, MaRS Centre, 101 College Street, Toronto, Ontario M5G 1L7, Canada.
authors.forename: Guodong
authors.initials: G
authors.lastname: Mao
authors.affiliation: Campbell Family Institute for Breast Cancer Research, University Health Network, TMDT East Tower, MaRS Centre, 101 College Street, Toronto, Ontario M5G 1L7, Canada.
authors.forename: Olga
authors.initials: O
authors.lastname: Plotnikova
authors.affiliation: Campbell Family Institute for Breast Cancer Research, University Health Network, TMDT East Tower, MaRS Centre, 101 College Street, Toronto, Ontario M5G 1L7, Canada.
authors.forename: Donald E
authors.initials: DE
authors.lastname: Awrey
authors.affiliation: Campbell Family Institute for Breast Cancer Research, University Health Network, TMDT East Tower, MaRS Centre, 101 College Street, Toronto, Ontario M5G 1L7, Canada.
authors.forename: Jacqueline M
authors.initials: JM
authors.lastname: Mason
authors.affiliation: Campbell Family Institute for Breast Cancer Research, University Health Network, TMDT East Tower, MaRS Centre, 101 College Street, Toronto, Ontario M5G 1L7, Canada.
authors.forename: Xin
authors.initials: X
authors.lastname: Wei
authors.affiliation: Campbell Family Institute for Breast Cancer Research, University Health Network, TMDT East Tower, MaRS Centre, 101 College Street, 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, University Health Network, TMDT East Tower, MaRS Centre, 101 College Street, Toronto, Ontario M5G 1L7, Canada.
authors.forename: Yi
authors.initials: Y
authors.lastname: Che
authors.affiliation: Campbell Family Institute for Breast Cancer Research, University Health Network, TMDT East Tower, MaRS Centre, 101 College Street, Toronto, Ontario M5G 1L7, Canada.
authors.forename: Reza
authors.initials: R
authors.lastname: Kiarash
authors.affiliation: Campbell Family Institute for Breast Cancer Research, University Health Network, TMDT East Tower, MaRS Centre, 101 College Street, Toronto, Ontario M5G 1L7, Canada.
authors.forename: Brian
authors.initials: B
authors.lastname: Madeira
authors.affiliation: Campbell Family Institute for Breast Cancer Research, University Health Network, TMDT East Tower, MaRS Centre, 101 College Street, Toronto, Ontario M5G 1L7, Canada.
authors.forename: Graham C
authors.initials: GC
authors.lastname: Fletcher
authors.affiliation: Campbell Family Institute for Breast Cancer Research, University Health Network, TMDT East Tower, MaRS Centre, 101 College Street, Toronto, Ontario M5G 1L7, Canada.
authors.forename: Tak W
authors.initials: TW
authors.lastname: Mak
authors.affiliation: Campbell Family Institute for Breast Cancer Research, University Health Network, TMDT East Tower, MaRS Centre, 101 College Street, Toronto, Ontario M5G 1L7, Canada.
authors.forename: Mark R
authors.initials: MR
authors.lastname: Bray
authors.affiliation: Campbell Family Institute for Breast Cancer Research, University Health Network, TMDT East Tower, MaRS Centre, 101 College Street, Toronto, Ontario M5G 1L7, Canada.
authors.forename: Henry W
authors.initials: HW
authors.lastname: Pauls
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D001549:Benzamides / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D001682:Biological Availability; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051381:Rats; D013329:Structure-Activity Relationship; D014227:Triazines / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D018797:Cell Cycle Proteins; D047428:Protein Kinase Inhibitors; D014227:Triazines; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; C075840:TTK protein, human
keywords: Antimitotic; Cancer; Inhibitor; Monopolar spindle 1 kinase (Mps1); Tyrosine Threonine Kinase (TTK)