Ammonia borane (AB), which has a very high hydrogen content by weight (19.6%), is attracting attention as a means of achieving efficient chemical hydrogen storage.1,2 Heating AB in the solid state, 3 ionic liquids 4 or the presence of acid 5 has been shown to induce the release of >1.0 equiv of H 2 over the course of several hours, and transition metal complexes of Rh, 6 Ni, 7 and Ir 8 have been shown to catalyze H 2 release under mild conditions. Notably, the Ni catalysts described by Baker release up to 2.8 equiv of H 2 , 7 an observation that has prompted a more detailed evaluation of their reaction mechanism.9a When considering strategies for dehydrogenation, AB is often compared to ethane.10 Computational predictions provide little mechanistic support for this analogy, however, 9,11 and in terms of local dipoles and reactivity AB may better be compared to methanol. Drawing from this analogy, we have discovered that ruthenium catalysts, originally developed for alcohol redox processes, 12 will induce the release of 1 equiv of H 2 from AB (up to 1.0 system wt %) within 5 min at room temperature with as little at 0.03 mol% Ru. Furthermore, 2 equiv of H 2 is rapidly released from highly concentrated (11 M) MeAB solutions at 22°C (ambient temperature), providing 3.0 system wt % hydrogen release. We have also found that by using an AB/MeAB mixture at 50°C, up to 3.6 system wt % H 2 can be released with 0.1 mol % Ru.An evaluation of several alcohol oxidation/reduction catalysts provided promising leads with complexes 1 to 6 (Figure 1). 13 In these studies, the precatalysts (0.1 mol%) were activated via treatment with KO t Bu (3 mol%) 13c in THF under inert atmosphere to generate the active ruthenium amide species prior to the addition of AB to the reaction vessel.14 Complexes 1 and 2 are particularly reactive even at 0.03 mol% Ru.14 Optimal outcomes are observed at high [AB] (5.0 M), an important parameter for maximal gravimetric H 2 density. In reactions with AB, we note the formation of an insoluble precipitate, which has been identified as the same polymeric aminoborane species obtained by Goldberg 8 and Manners. 15 The dehydrogenation of methylammonia-borane (MeAB) was also evaluated. 6 Under conditions similar to those employed for AB dehydrogenation, 0.5 mol% 1 induced the release of up to 2.0 equiv of H 2 from MeAB in ∼10 min (Figure 2). 16 These reactions are characterized by a very rapid release of the first equivalent of H 2 (occurring in less than 10 s), generating poly(N-methylaminoborane).15 This is followed by a slower release of the second equivalent over ∼10 min. 17 Since no insoluble precipitate is observed, more concentrated conditions (11 M [MeAB]) may be employed, increasing the system % H 2 to 3% (1.9 equiv of H 2 released). To further maximize the gravimetric H 2 density, AB-MeAB mixtures were evaluated.18 Initial results using a 1:1 AB/MeAB mixture at 50°C indicate that 3.6 system wt % H 2 release can be achieved with 0.1 mol% 1 under solvent-free conditions. 16As a preliminary probe i...

The biological and medicinal impacts of proteolysis-targeting chimeras (PROTACs) and related chimeric molecules that effect intracellular degradation of target proteins via ubiquitin ligase-mediated ubiquitination continue to grow. However, these chimeric entities are relatively large compounds that often possess molecular characteristics, which may compromise oral bioavailability, solubility, and/or in vivo pharmacokinetic properties. We therefore explored the conjugation of such molecules to monoclonal antibodies using technologies originally developed for cytotoxic payloads so as to provide alternate delivery options for these novel agents. In this report, we describe the first phase of our systematic development of antibody–drug conjugates (ADCs) derived from bromodomain-containing protein 4 (BRD4)-targeting chimeric degrader entities. We demonstrate the antigen-dependent delivery of the degrader payloads to PC3-S1 prostate cancer cells along with related impacts on MYC transcription and intracellular BRD4 levels. These experiments culminate with the identification of one degrader conjugate, which exhibits antigen-dependent antiproliferation effects in LNCaP prostate cancer cells.

NF-κB-inducing kinase (NIK) mediates non-canonical NF-κB signaling downstream of multiple TNF family members, including BAFF, TWEAK, CD40, and OX40, which are implicated in the pathogenesis of systemic lupus erythematosus (SLE). Here, we show that experimental lupus in NZB/W F1 mice can be treated with a highly selective and potent NIK small molecule inhibitor. Both in vitro as well as in vivo, NIK inhibition recapitulates the pharmacological effects of BAFF blockade, which is clinically efficacious in SLE. Furthermore, NIK inhibition also affects T cell parameters in the spleen and proinflammatory gene expression in the kidney, which may be attributable to inhibition of OX40 and TWEAK signaling, respectively. As a consequence, NIK inhibition results in improved survival, reduced renal pathology, and lower proteinuria scores. Collectively, our data suggest that NIK inhibition is a potential therapeutic approach for SLE.

No abstract

Dysfunctional signaling through the phosphoinositide 3-kinase (PI3K)/AKT/mTOR pathway leads to uncontrolled tumor proliferation. In the course of the discovery of novel benzoxepin PI3K inhibitors, we observed a strong dependency of in vivo antitumor activity on the free-drug exposure. By lowering the intrinsic clearance, we derived a set of imidazobenzoxazepin compounds that showed improved unbound drug exposure and effectively suppressed growth of tumors in a mouse xenograft model at low drug dose levels. One of these compounds, GDC-0032 (11l), was progressed to clinical trials and is currently under phase I evaluation as a potential treatment for human malignancies.