We report the discovery and characterization of SM-406 (compound 2), a potent and orally bioavailable Smac mimetic and an antagonist of the inhibitor of apoptosis proteins (IAPs). This compound binds to XIAP, cIAP1 and cIAP2 proteins with Ki values of 66.4 nM, 1.9 nM and 5.1 nM, respectively. Compound 2 effectively antagonizes XIAP BIR3 protein in a cell-free functional assay, induces rapid degradation of cellular cIAP1 protein and inhibits cancer cell growth in various human cancer cell lines. It has good oral bioavailability in mice, rats, non-human primates and dogs, is highly effective in induction of apoptosis in xenograft tumors and is capable of complete inhibition of tumor growth. Compound 2 is currently in Phase I clinical trials for the treatment of human cancer.

The permafrost organic carbon (OC) stock is of global significance because of its large pool size and the potential positive feedback to climate warming. However, due to the lack of systematic field observations and appropriate upscaling methodologies, substantial uncertainties exist in the permafrost OC budget, which limits our understanding of the fate of frozen carbon in a warming world. In particular, the lack of comprehensive estimates of OC stocks across alpine permafrost means that current knowledge on this issue remains incomplete. Here, we evaluated the pool size and spatial variations of permafrost OC stock to 3 m depth on the Tibetan Plateau by combining systematic measurements from a substantial number of pedons (i.e. 342 three-metre-deep cores and 177 50-cm-deep pits) with a machine learning technique (i.e. support vector machine, SVM). We also quantified uncertainties in permafrost carbon budget by conducting Monte Carlo simulations. Our results revealed that the combination of systematic measurements with the SVM model allowed spatially explicit estimates to be made. The OC density (OC amount per unit area, OCD) exhibited a decreasing trend from the south-eastern to the north-western plateau, with the exception that OCD in the swamp meadow was substantially higher than that in surrounding regions. Our results also demonstrated that Tibetan permafrost stored a large amount of OC in the top 3 m, with the median OC pool size being 15.31 Pg C (interquartile range: 13.03-17.77 Pg C). 44% of OC occurred in deep layers (i.e. 100-300 cm), close to the proportion observed across the northern circumpolar permafrost region. The large carbon pool size together with significant permafrost thawing suggests a risk of carbon emissions and positive climate feedback across the Tibetan alpine permafrost region.

One hallmark of cancer cells is their compromised ability to undergo apoptosis, or programmed cell death. Strategies targeting key apoptosis regulators with the goal of overcoming resistance to apoptosis have significant therapeutic potential for the development of new classes of anticancer drugs. Smac is a pro-apoptotic protein which, by binding to the inhibitor of apoptosis proteins (IAPs), antagonizes their cellular anti-apoptotic function. It interacts with IAPs through its four N-terminal amino acid residues (AVPI). Small molecules that mimic this four residue sequence are being studied as the basis of a new therapeutic strategy for the treatment of human cancers and other diseases. In this Account, we provide an overview of the design, synthesis and evaluation on both peptidic and non-peptidic small-molecule Smac mimetics.

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