The transcription factors NF-κB and IFN control important signaling cascades and mediate the expression of a number of important pro-inflammatory cytokines, adhesion molecules, growth factors and anti-apoptotic survival proteins. IκB kinase (IKK) and IKK-related kinases (IKKε and TBK1) are key regulators of these biological pathways and, as such, modulators of these enzymes may be useful in the treatment of inflammatory diseases and cancer. We have reviewed the most recent IKK patent literature (2008-2012), added publications of interest overlooked in previous patent reviews and identified all the players involved in small-molecule inhibitors of the IKKs. This will provide the reader with a decisive summary of the IKK arena, a field that has reached maturity over a decade of research.

Sphingosine kinase enzymes (SK1 and SK2) catalyse the conversion of sphingosine into sphingosine 1-phosphate and play a key role in lipid signaling and cellular responses. Mapping of isoform amino acid sequence differences for SK2 onto the recently available crystal structures of SK1 suggests that subtle structural differences exist in the foot of the lipid-binding 'J-channel' in SK2, the structure of which has yet to be defined by structural biology techniques. We have probed these isoform differences with a ligand series derived from the potent SK1-selective inhibitor, PF-543. Here we show how it is possible, even with relatively conservative changes in compound structure, to systematically tune the activity profile of a ligand from ca. 100-fold SK1-selective inhibition, through equipotent SK1/SK2 inhibition, to reversed 100-fold SK2 selectivity, with retention of nanomolar potency. -phosphate (S1P) is a key signalling lipid derived from sphingosine (Sph) by the action of sphingosine kinases (SK1 and SK2). S1P is transported to the extracellular environment, where it functions as a ligand for a family of five S1P-specific G protein coupled receptors (S1P 1-5 ), but it also acts on specific intracellular target proteins, such as histone deacetylases 1/2 (HDAC1/2). 1, 2 Irreversible cleavage of S1P is catalysed by S1P lyase, producing (E)-2hexadecenal and phosphoethanolamine, 3 but S1P is also reversibly dephosphorylated by S1P phosphatase to regenerate Sph, 4-6 levels of which are additionally influenced by flux through the ceramide (Cer) synthesis pathway. 7 The effects of S1P on cell function favour proliferation, migration, differentiation and survival and are generally opposed by Cer, which induces apoptosis, senescence and growth arrest. 8,9 As a consequence the concept of the 'sphingolipid rheostat' was proposed, 10,11 in which the inter-conversion of Cer via Sph to S1P controls cellular fate (recently reviewed 12,13 ). Altered S1P signalling has been associated with numerous pathophysiologies, including cancer, cardiovascular disease, neurodegenerative conditions, diabetes and inflammatory disease. 14 The possibility of manipulating the sphingolipid rheostat for therapeutic purposes has therefore provided a rationale for exploring the development of SK inhibitors and their potential to reduce S1P formation and signalling and to raise pro-apoptotic Cer levels.The SK1 and SK2 enzymes are encoded by distinct genes and differ in their subcellular localisation, biochemical properties and functions; there are three N-terminal variants of SK1 and two N-terminal variants of SK2. 15,16 A number of classes of SK inhibitors have emerged in the last two decades, including the recent discovery of an ATP-competitive SK inhibitor chemotype that decreases cellular S1P levels, elevates Sph/Cer, induces apoptosis, and that inhibits cell proliferation and colony formation. 17 Most work to date, however, has focused on the development Sph-competitive inhibitors. This includes the development of inhibitors selective for SK1 t...

Society urgently needs new, effective medicines for the treatment of tuberculosis. To kick-start the required hit-to-lead campaigns, the libraries of pharmaceutical companies have recently been evaluated for starting points. The GlaxoSmithKline (GSK) library yielded many high-quality hits and the associated data were placed in the public domain to stimulate engagement by the wider community. One such series, the Spiro compounds, are described here. The compounds were explored by a combination of traditional in-house research and open source methods. The series benefits from a particularly simple structure and a short associated synthetic chemistry route. Many members of the series displayed striking potency and low toxicity, and highly promising in vivo activity in a mouse model was confirmed with one of the analogs. Ultimately the series was discontinued due to concerns over safety, but the associated data remain public domain, empowering others to resume the series if the perceived deficiencies can be overcome. Parameter 1 Mtb H37Rv MIC90 (µM) 0.30 Mtb MIC90 (µM) (108 strains) 0.60 Intracellular H37Rv MIC80 (µM) 0.25 Antibacterial panel IC50 (µM) ≥16 Mammalian cell (HepG2) Tox50 (µM) 36 clogP 2.99 CLint (mL/min•g) mouse microsomes >30 CLint (mL/min•g) human microsomes 25 Solubility CLND (µM) 266 The compound's intra-macrophage activity, selectivity for mycobacteria vs. other bacterial species, and potency against a broad panel of clinical isolates including MDR and XDR strains, in vitro-cidal behavior and a low frequency of spontaneous resistance 13a suggested a highly promising antitubercular profile. The low microsomal stability was a concern and required improvement. In this paper, we report our efforts to optimize this family of compounds through the synthesis of analogs aimed at retaining the antitubercular potency while improving the overall profile for the series. RESULTS AND DISCUSSION Synthesis and In Vitro Evaluation of Analogs Aiming to explore the chemical space of the series, a library of novel compounds was synthesized and evaluated. The compounds were isolated either as free amines or as salts (hydrochloride or

IKKβ plays a central role in the canonical NF-kB pathway, which has been extensively characterized. The role of IKKα in the noncanonical NF-kB pathway, and indeed in the canonical pathway as a complex with IKKβ, is less well understood. One major reason for this is the absence of chemical tools designed as selective inhibitors for IKKα over IKKβ. Herein, we report for the first time a series of novel, potent, and selective inhibitors of IKKα. We demonstrate effective target engagement and selectivity with IKKα in U2OS cells through inhibition of IKKα-driven p100 phosphorylation in the noncanonical NF-kB pathway without affecting IKKβ-dependent IKappa-Bα loss in the canonical pathway. These compounds represent the first chemical tools that can be used to further characterize the role of IKKα in cellular signaling, to dissect this from IKKβ and to validate it in its own right as a target in inflammatory diseases.

The stereochemical outcome of the Lewis acid-mediated glycolate addition of the titanium enolates from protected N-hydroxyacetyl-4-isopropyl-1,3-thiazolidine-2-thiones to dimethyl and dibenzyl acetals depends on the hydroxyl protecting group. Particularly, the pivaloyl protected glycolate derivative provides the reluctant anti adducts in high yields and diastereomeric ratios, which can be isolated and further converted in enantiomerically pure form to β-methoxy or β-benzyloxy α-pivaloyloxy carbonyl fragments in a straightforward manner.