Discovery of a Potent, Orally Bioavailable PI4KIIIβ Inhibitor (UCB9608) Able To Significantly Prolong Allogeneic Organ Engraftment in Vivo
J.T. Reuberson
1
,
Helen Horsley
1
,
Richard J Franklin
1
,
Daniel Ford
1
,
Judi Neuss
1
,
Daniel Brookings
1
,
Qiuya Huang
2
,
Bart Vanderhoydonck
2
,
Ling-Jie Gao
2
,
Mi Yeon Jang
2
,
Piet Herdewijn
2
,
Anant Ghawalkar
3
,
Farnaz Fallah-Arani
1
,
Adnan R. Khan
1
,
Jamie Henshall
1
,
Mark Jairaj
1
,
Sarah Malcolm
1
,
Eleanor Ward
1
,
Lindsay Shuttleworth
1
,
Lin Yuan
2
,
Shengqiao Li
2
,
Thierry Louat
2
,
MARK WAER
2
,
J. T. Herman
2
,
Andrew Payne
1
,
Tom Ceska
1
,
Carl Doyle
1
,
Will Pitt
1
,
Mark Calmiano
1
,
Martin Augustin
4
,
Stefan Steinbacher
4
,
Alfred Lammens
4
,
Rodger Allen
1
1
UCB Pharma, 208 Bath Road, Slough, Berkshire SL1 3WE, United Kingdom
|
3
SAI Life Sciences Ltd, International Biotech Park, Hinjewadi, Pune 411 057, India
|
4
Proteros biostructures GmbH, Bunsenstrasse 7a, 82152 Martinsried, Germany
|
Publication type: Journal Article
Publication date: 2018-06-28
scimago Q1
wos Q1
SJR: 1.801
CiteScore: 11.5
Impact factor: 6.8
ISSN: 00222623, 15204804
PubMed ID:
29952567
Drug Discovery
Molecular Medicine
Abstract
The primary target of a novel series of immunosuppressive 7-piperazin-1-ylthiazolo[5,4- d]pyrimidin-5-amines was identified as the lipid kinase, PI4KIIIβ. Evaluation of the series highlighted their poor solubility and unwanted off-target activities. A medicinal chemistry strategy was put in place to optimize physicochemical properties within the series, while maintaining potency and improving selectivity over other lipid kinases. Compound 22 was initially identified and profiled in vivo, before further modifications led to the discovery of 44 (UCB9608), a vastly more soluble, selective compound with improved metabolic stability and excellent pharmacokinetic profile. A co-crystal structure of 44 with PI4KIIIβ was solved, confirming the binding mode of this class of inhibitor. The much-improved in vivo profile of 44 positions it as an ideal tool compound to further establish the link between PI4KIIIβ inhibition and prolonged allogeneic organ engraftment, and suppression of immune responses in vivo.
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Total citations:
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GOST
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Reuberson J. et al. Discovery of a Potent, Orally Bioavailable PI4KIIIβ Inhibitor (UCB9608) Able To Significantly Prolong Allogeneic Organ Engraftment in Vivo // Journal of Medicinal Chemistry. 2018. Vol. 61. No. 15. pp. 6705-6723.
GOST all authors (up to 50)
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Reuberson J., Horsley H., Franklin R. J., Ford D., Neuss J., Brookings D., Huang Q., Vanderhoydonck B., Gao L., Jang M. Y., Herdewijn P., Ghawalkar A., Fallah-Arani F., Khan A. R., Henshall J., Jairaj M., Malcolm S., Ward E., Shuttleworth L., Yuan L., Li S., Louat T., WAER M., Herman J. T., Payne A., Ceska T., Doyle C., Pitt W., Calmiano M., Augustin M., Steinbacher S., Lammens A., Allen R. Discovery of a Potent, Orally Bioavailable PI4KIIIβ Inhibitor (UCB9608) Able To Significantly Prolong Allogeneic Organ Engraftment in Vivo // Journal of Medicinal Chemistry. 2018. Vol. 61. No. 15. pp. 6705-6723.
Cite this
RIS
Copy
TY - JOUR
DO - 10.1021/acs.jmedchem.8b00521
UR - https://doi.org/10.1021/acs.jmedchem.8b00521
TI - Discovery of a Potent, Orally Bioavailable PI4KIIIβ Inhibitor (UCB9608) Able To Significantly Prolong Allogeneic Organ Engraftment in Vivo
T2 - Journal of Medicinal Chemistry
AU - Reuberson, J.T.
AU - Horsley, Helen
AU - Franklin, Richard J
AU - Ford, Daniel
AU - Neuss, Judi
AU - Brookings, Daniel
AU - Huang, Qiuya
AU - Vanderhoydonck, Bart
AU - Gao, Ling-Jie
AU - Jang, Mi Yeon
AU - Herdewijn, Piet
AU - Ghawalkar, Anant
AU - Fallah-Arani, Farnaz
AU - Khan, Adnan R.
AU - Henshall, Jamie
AU - Jairaj, Mark
AU - Malcolm, Sarah
AU - Ward, Eleanor
AU - Shuttleworth, Lindsay
AU - Yuan, Lin
AU - Li, Shengqiao
AU - Louat, Thierry
AU - WAER, MARK
AU - Herman, J. T.
AU - Payne, Andrew
AU - Ceska, Tom
AU - Doyle, Carl
AU - Pitt, Will
AU - Calmiano, Mark
AU - Augustin, Martin
AU - Steinbacher, Stefan
AU - Lammens, Alfred
AU - Allen, Rodger
PY - 2018
DA - 2018/06/28
PB - American Chemical Society (ACS)
SP - 6705-6723
IS - 15
VL - 61
PMID - 29952567
SN - 0022-2623
SN - 1520-4804
ER -
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BibTex (up to 50 authors)
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@article{2018_Reuberson,
author = {J.T. Reuberson and Helen Horsley and Richard J Franklin and Daniel Ford and Judi Neuss and Daniel Brookings and Qiuya Huang and Bart Vanderhoydonck and Ling-Jie Gao and Mi Yeon Jang and Piet Herdewijn and Anant Ghawalkar and Farnaz Fallah-Arani and Adnan R. Khan and Jamie Henshall and Mark Jairaj and Sarah Malcolm and Eleanor Ward and Lindsay Shuttleworth and Lin Yuan and Shengqiao Li and Thierry Louat and MARK WAER and J. T. Herman and Andrew Payne and Tom Ceska and Carl Doyle and Will Pitt and Mark Calmiano and Martin Augustin and Stefan Steinbacher and Alfred Lammens and Rodger Allen},
title = {Discovery of a Potent, Orally Bioavailable PI4KIIIβ Inhibitor (UCB9608) Able To Significantly Prolong Allogeneic Organ Engraftment in Vivo},
journal = {Journal of Medicinal Chemistry},
year = {2018},
volume = {61},
publisher = {American Chemical Society (ACS)},
month = {jun},
url = {https://doi.org/10.1021/acs.jmedchem.8b00521},
number = {15},
pages = {6705--6723},
doi = {10.1021/acs.jmedchem.8b00521}
}
Cite this
MLA
Copy
Reuberson, J.T., et al. “Discovery of a Potent, Orally Bioavailable PI4KIIIβ Inhibitor (UCB9608) Able To Significantly Prolong Allogeneic Organ Engraftment in Vivo.” Journal of Medicinal Chemistry, vol. 61, no. 15, Jun. 2018, pp. 6705-6723. https://doi.org/10.1021/acs.jmedchem.8b00521.