title: Discovery of Pyrazolo[1,5-a]pyrimidine TTK Inhibitors: CFI-402257 is a Potent, Selective, Bioavailable Anticancer Agent.
abstract: This work describes a scaffold hopping exercise that begins with known imidazo[1,2-a]pyrazines, briefly explores pyrazolo[1,5-a][1,3,5]triazines, and ultimately yields pyrazolo[1,5-a]pyrimidines as a novel class of potent TTK inhibitors. An X-ray structure of a representative compound is consistent with 1(1)/2 type inhibition and provides structural insight to aid subsequent optimization of in vitro activity and physicochemical and pharmacokinetic properties. Incorporation of polar moieties in the hydrophobic and solvent accessible regions modulates physicochemical properties while maintaining potency. Compounds with enhanced oral exposure were identified for xenograft studies. The work culminates in the identification of a potent (TTK K i = 0.1 nM), highly selective, orally bioavailable anticancer agent (CFI-402257) for IND enabling studies.
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: 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: Narendra Kumar
authors.initials: NK
authors.lastname: Patel
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: Peter B
authors.initials: PB
authors.lastname: Sampson
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: 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: 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 Cancer Research Institute, University Health Network , Princess Margaret Cancer Center, 610 University Avenue, Toronto, Ontario M5G 2C4, Canada.
authors.forename: Wei
authors.initials: W
authors.lastname: Qiu
authors.affiliation: Campbell Family Cancer Research Institute, University Health Network , Princess Margaret Cancer Center, 610 University Avenue, Toronto, Ontario M5G 2C4, Canada.
authors.forename: Nickolay Y
authors.initials: NY
authors.lastname: Chirgadze
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: 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
keywords: 11/2 type inhibitors; CFI-402257; TTK inhibitors; pyrazolo[1,5-a]pyrimidines