Discovery of Pyrazolo[1,5-a]pyrimidine TTK Inhibitors: CFI-402257 is a Potent, Selective, Bioavailable Anticancer Agent
Yong Liu
1
,
Radoslaw Laufer
1
,
Narendra Kumar Patel
1
,
Grace Ng
1
,
Peter B. Sampson
1
,
Sze Wan Li
1
,
Yunhui Lang
1
,
Miklós Fehér
1
,
Richard Brokx
1
,
Irina Beletskaya
1
,
Richard Hodgson
1
,
Olga Plotnikova
1
,
Donald E. Awrey
1
,
Wei Qiu
2
,
Nickolay Y. Chirgadze
2
,
Jacqueline M. Mason
1
,
Wei Xin
1
,
Dan Chi Chia Lin
1
,
Yi Che
1
,
Reza Kiarash
1
,
Graham C Fletcher
1
,
Tak W. Mak
1
,
Mark R. Bray
1
,
Henry W Pauls
1
1
Campbell
Family Institute for Breast Cancer Research, University Health Network, TMDT East Tower, MaRS Centre, 101 College Street, Toronto, Ontario M5G 1L7, Canada
|
Publication type: Journal Article
Publication date: 2016-05-06
scimago Q1
wos Q2
SJR: 0.805
CiteScore: 5.8
Impact factor: 4.0
ISSN: 19485875
PubMed ID:
27437075
Organic Chemistry
Drug Discovery
Biochemistry
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.
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Citations from 2024:
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GOST
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Liu Y. et al. Discovery of Pyrazolo[1,5-a]pyrimidine TTK Inhibitors: CFI-402257 is a Potent, Selective, Bioavailable Anticancer Agent // ACS Medicinal Chemistry Letters. 2016. Vol. 7. No. 7. pp. 671-675.
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Liu Y., Laufer R., Patel N. K., Ng G., Sampson P. B., Li S. W., Lang Y., Fehér M., Brokx R., Beletskaya I., Hodgson R., Plotnikova O., Awrey D. E., Qiu W., Chirgadze N. Y., Mason J. M., Xin W., Lin D. C. C., Che Y., Kiarash R., Fletcher G. C., Mak T. W., Bray M. R., Pauls H. W. Discovery of Pyrazolo[1,5-a]pyrimidine TTK Inhibitors: CFI-402257 is a Potent, Selective, Bioavailable Anticancer Agent // ACS Medicinal Chemistry Letters. 2016. Vol. 7. No. 7. pp. 671-675.
Cite this
RIS
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TY - JOUR
DO - 10.1021/acsmedchemlett.5b00485
UR - https://doi.org/10.1021/acsmedchemlett.5b00485
TI - Discovery of Pyrazolo[1,5-a]pyrimidine TTK Inhibitors: CFI-402257 is a Potent, Selective, Bioavailable Anticancer Agent
T2 - ACS Medicinal Chemistry Letters
AU - Liu, Yong
AU - Laufer, Radoslaw
AU - Patel, Narendra Kumar
AU - Ng, Grace
AU - Sampson, Peter B.
AU - Li, Sze Wan
AU - Lang, Yunhui
AU - Fehér, Miklós
AU - Brokx, Richard
AU - Beletskaya, Irina
AU - Hodgson, Richard
AU - Plotnikova, Olga
AU - Awrey, Donald E.
AU - Qiu, Wei
AU - Chirgadze, Nickolay Y.
AU - Mason, Jacqueline M.
AU - Xin, Wei
AU - Lin, Dan Chi Chia
AU - Che, Yi
AU - Kiarash, Reza
AU - Fletcher, Graham C
AU - Mak, Tak W.
AU - Bray, Mark R.
AU - Pauls, Henry W
PY - 2016
DA - 2016/05/06
PB - American Chemical Society (ACS)
SP - 671-675
IS - 7
VL - 7
PMID - 27437075
SN - 1948-5875
ER -
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@article{2016_Liu,
author = {Yong Liu and Radoslaw Laufer and Narendra Kumar Patel and Grace Ng and Peter B. Sampson and Sze Wan Li and Yunhui Lang and Miklós Fehér and Richard Brokx and Irina Beletskaya and Richard Hodgson and Olga Plotnikova and Donald E. Awrey and Wei Qiu and Nickolay Y. Chirgadze and Jacqueline M. Mason and Wei Xin and Dan Chi Chia Lin and Yi Che and Reza Kiarash and Graham C Fletcher and Tak W. Mak and Mark R. Bray and Henry W Pauls},
title = {Discovery of Pyrazolo[1,5-a]pyrimidine TTK Inhibitors: CFI-402257 is a Potent, Selective, Bioavailable Anticancer Agent},
journal = {ACS Medicinal Chemistry Letters},
year = {2016},
volume = {7},
publisher = {American Chemical Society (ACS)},
month = {may},
url = {https://doi.org/10.1021/acsmedchemlett.5b00485},
number = {7},
pages = {671--675},
doi = {10.1021/acsmedchemlett.5b00485}
}
Cite this
MLA
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Liu, Yong, et al. “Discovery of Pyrazolo[1,5-a]pyrimidine TTK Inhibitors: CFI-402257 is a Potent, Selective, Bioavailable Anticancer Agent.” ACS Medicinal Chemistry Letters, vol. 7, no. 7, May. 2016, pp. 671-675. https://doi.org/10.1021/acsmedchemlett.5b00485.