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

The primary target of a novel series of immuno­suppressive 7-piperazin-1-yl­thiazolo­[5,4-<i>d</i>]­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 <b>22</b> was initially identified and profiled <i>in vivo</i>, before further modifications led to the discovery of <b>44</b> (UCB9608), a vastly more soluble, selective compound with improved metabolic stability and excellent pharmaco­kinetic profile. A co-crystal structure of <b>44</b> with PI4KIIIβ was solved, confirming the binding mode of this class of inhibitor. The much-improved <i>in vivo</i> profile of <b>44</b> 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 <i>in vivo