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

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.

A New Lead Identification Strategy: Screening an sp3‐rich and Lead‐like Compound Library Composed of 7‐Azanorbornane Derivatives

“…Compounds with higher Fsp 3 values tend to possess more drug‐like properties such as high solubility and low promiscuity, and these compounds are more likely to achieve clinical success. Indeed, by enhancing the Fsp 3 values in the course of lead optimization, many research groups succeeded in improving physical properties of candidate compounds …”

Intratumoral immunotherapy with anti-PD-1 and TLR9 agonist induces systemic antitumor immunity without accelerating rejection of cardiac allografts

“…Heterotopic cardiac transplantation into the neck of allogenic mice by microsurgical techniques was done as described previously. 13 Graft survival was assessed twice daily by inspection and palpation, and rejection was diagnosed by cessation of ventricular contractions and confirmed by histologic examination.…”

“…13 Vehicle consisting of 1% myth cellulose and 0.1 Tween 80 was used as controls. 13 The PI4Ki solution and vehicle were kindly prepared and provided by UCB.…”

“…Long-term survival and tolerance of the cardiac allograft were induced after a 2-week therapy with PI4Ki UCB9608. 13 First, we evaluated i.t. vs i.p.…”

“…We have induced long-term survival and tolerance of heart allografts in C57BL/6 or Balb/c mice by various immunosuppressive regimens including the treatment with PI4KIIIβ inhibitors. 13 Here we investigated the effect of immunotherapy with anti-PD-1 and toll like receptor 9 (TLR9) agonists on anti-tumor immunity and transplant immunoreactivity in these models.…”