2. Academic Validation
  3. Discovery of a Potent, Orally Bioavailable PI4KIIIβ Inhibitor (UCB9608) Able To Significantly Prolong Allogeneic Organ Engraftment in Vivo

Discovery of a Potent, Orally Bioavailable PI4KIIIβ Inhibitor (UCB9608) Able To Significantly Prolong Allogeneic Organ Engraftment in Vivo

  • J Med Chem. 2018 Aug 9;61(15):6705-6723. doi: 10.1021/acs.jmedchem.8b00521.
James 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,  Yuan Lin 2,  Shengqiao Li 2,  Thierry Louat 2,  Mark Waer 2,  Jean 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
Affiliations

Affiliations

  • 1 UCB Pharma , 208 Bath Road , Slough , Berkshire SL1 3WE , United Kingdom.
  • 2 Interface Valorization Platform , KU Leuven , Campus St.-Rafaël, Blok I, 8°, Kapucijnenvoer 33 B 7001 , 3000 Leuven , Belgium.
  • 3 SAI Life Sciences Ltd , International Biotech Park , Hinjewadi, Pune 411 057 , India.
  • 4 Proteros Biostructures GmbH , Bunsenstrasse 7a , 82152 Martinsried , Germany.
PMID: 29952567 DOI: 10.1021/acs.jmedchem.8b00521
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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