Background: Sclerostin, an inhibitor of Wnt signaling, binds to the ␤-propeller domain-containing Wnt co-receptors LRP6 and LRP4. Results: An NXI motif in sclerostin mediates interactions with LRP6 (but not LRP4) and blocks Wnt1 signaling. Conclusion:The sclerostin/LRP6 interaction shares features with the well characterized nidogen/laminin interaction. Significance: NXI motifs are important in mediating interactions with ␤-propeller containing proteins.

Phosphoinositide 3-kinases (PI3K) are key signaling enzymes regulating cellular survival, development, and function. Expression of the PI3K isoform is largely restricted to leukocytes and it plays a key role in immune cell development and function. Seletalisib is a novel small-molecule inhibitor of PI3K that was evaluated in biochemical assays, cellular assays of adaptive and innate immunity, and an in vivo rat model of inflammation. Our findings show that seletalisib is a potent, ATP-competitive, and selective PI3K inhibitor able to block protein kinase B (AKT) phosphorylation following activation of the B-cell receptor in a B-cell line. Moreover, seletalisib inhibited -formyl peptide-stimulated but not phorbol myristate acetate-stimulated superoxide release from human neutrophils, consistent with a PI3K-specific activity. No indications of cytotoxicity were observed in peripheral blood mononuclear cells (PBMCs) or other cell types treated with seletalisib. Findings from cellular assays of adaptive immunity demonstrated that seletalisib blocks human T-cell production of several cytokines from activated T-cells. Additionally, seletalisib inhibited B-cell proliferation and cytokine release. In human whole blood assays, seletalisib inhibited CD69 expression upon B-cell activation and anti-IgE-mediated basophil degranulation. Seletalisib showed dose-dependent inhibition in an in vivo rat model of anti-CD3-antibody-induced interleukin 2 release. Collectively, these data characterize seletalisib as a selective PI3K inhibitor and potential therapeutic candidate for the treatment of B-cell malignancies and autoimmune diseases driven by dysregulated proinflammatory cytokine secretion.

The enantiopure bidentate indenyl-phosphine ligands (1S)-[2-(3H-inden-1-yl)-1-phenylethyl]diphenylphosphine (9) and [(2R)-2-cyclohexyl-2-(3H-inden-1-yl)ethyl]diphenylphosphine (18) were synthesized in 20% yield and three steps from (R)-styrene oxide and in 61% yield and four steps from vinylcyclohexane, respectively. In both cases ring opening of a spirocyclopropane-1,1′-indene with potassium diphenylphosphide was a key step. Addition of the lithium salts of 9 and 18 to [Rh(µ-Cl)(CO) 2 ] 2 gave (η 5 :η 1 -indenyl-CH 2 CH(Ph)PPh 2 )RhCO and (η 5 :η 1 -indenyl-CH(Cy)CH 2 PPh 2 )RhCO as 75:25 and 78:22 mixtures of diastereoisomers, from which the major complexes were readily obtained by crystallization. The chiral centers in the linking chain β and R to the indenyl ring had thus induced good planar chirality of the complexed indenyl moiety. Both complexes were characterized by X-ray crystallography.

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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.