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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ABSTRACT:The phosphatidylinositol 3-kinase (PI3K) signaling pathway plays important roles in cell proliferation, growth, and survival. Hyperactivated PI3K is frequently found in a wide variety of human cancers, validating it as a promising target for cancer therapy. We determined the crystal structure of the human PI3Kα−PI103 complex to unravel molecular interactions. Based on the structure, substitution at the R 1 position of the phenol portion of PI103 was demonstrated to improve binding affinity via forming a new H-bond with Lys802 at the bottom of the ATP catalytic site. Interestingly, the crystal structure of the PI3Kα−9d complex revealed that the flexibility of Lys802 can also induce additional space at the catalytic site for further modification. Thus, these crystal structures provide a molecular basis for the strong and specific interactions and demonstrate the important role of Lys802 in the design of novel PI3Kα inhibitors. KEYWORDS: PI3K, PI103, crystal structure, drug design, cancer therapy T he lipid kinase family of phosphatidylinositol 3-kinases (PI3Ks) plays pivotal roles in many cellular processes, including proliferation, survival, differentiation, and metabolism. 1−3 Class I PI3K, the best physiologically, biochemically, and structurally characterized member of the PI3K family, consists of four isoforms, α, β, γ, and δ. Each isoform is a heterodimer that comprises a p110 catalytic subunit and a p85 regulatory subunit. Upon insulin and growth factor stimulation, PI3Ks phosphorylate phosphatidylinositol-3,4-bisphosphate (PIP2) to produce phosphatidylinositol-3,4,5-triphosphate (PIP3). The cellular level of PIP3 is also tightly regulated by phosphatases, such as the phosphatase and tensin homologue (PTEN), which dephosphorylates PIP3 back to PIP2. 4,5 The PI3K pathway is frequently deregulated in a wide range of tumor types as a result of hyperactivation of upstream growth factor signaling, mutation, or loss of PTEN, 6 and oncogenic mutations in PIK3CA, 7 which provides further evidence of the role of PI3K in tumorigenesis. Moreover, accumulating evidence indicates that hyperactivation of PI3Kα is inextricably linked to cancer survival and resistance to existing therapies in a great proportion of human cancers. 8 Therefore, targeting PI3Ks with small-molecular-weight inhibitors provides an attractive opportunity for cancer therapy and for overcoming resistance to current therapies, and thus, significant efforts have recently been made to develop PI3K inhibitors. 9 With multiple ongoing efforts in academic and industrial organizations to develop clinically relevant inhibitors against PI3K, a number of inhibitors have already entered clinical trials. 2,10 PI103 is one of the first synthesized PI3K inhibitors; it belongs to the pyridinylfuranopyrimidine class and inhibits PI3K in an ATP-competitive manner with selectivity toward PI3Kα. 11 PI103 has already demonstrated significant antitumor activity against several human tumor xenografts, especially those with well-established abnormalities in the P...

Aim Root production and turnover play a key role in regulating carbon (C) flow in terrestrial ecosystems. However, a general pattern reflecting the responses of roots to increasing nitrogen (N) input has yet to be described. Location Global terrestrial ecosystems. Methods We conducted a meta‐analysis to assess the central tendencies of root production, turnover rate and standing crop with respect to the experimental addition of N. We evaluated the effect of the form of N, root diameter and climatic (mean annual temperature, MAT; mean annual precipitation, MAP), biotic (ecosystem type, plant type and forest stand age) and forcing factors (experimental duration, N addition rate and cumulative amount of N) on the variations in root response. Results Globally, the addition of N significantly decreased root production and turnover rate but had only a minor impact on root standing crop. In different ecosystems, the three root variables exhibited heterogeneous responses to N enrichment. Additionally, root production and turnover rate responded distinctly to diverse forms of N. The responses of root production and turnover rate to the addition of N were generally positively correlated with MAT and MAP but negatively related to forest stand age and experimental duration. The response pattern of root standing crop was negatively affected by MAT, MAP and forest stand age. However, none of the three root parameters had any obvious correlations with N addition rate or cumulative amount of N. Main conclusions Our results demonstrate that, on aggregate, the addition of N decreased root production and turnover rate at the global scale. These root response patterns and the regulatory factors can be incorporated into earth system models to improve the prediction of belowground C dynamics.

Unprecedented levels of nitrogen (N) have entered terrestrial ecosystems over the past century, which substantially influences the carbon (C) exchange between the atmosphere and biosphere. Temperature and moisture are generally regarded as the major controllers over the N effects on ecosystem C uptake and release. N-phosphorous (P) stoichiometry regulates the growth and metabolisms of plants and soil organisms, thereby affecting many ecosystem C processes. However, it remains unclear how the N-induced shift in the plant N:P ratio affects ecosystem production and C fluxes and its relative importance. We conducted a field manipulative experiment with eight N addition levels in a Tibetan alpine steppe and assessed the influences of N on aboveground net primary production (ANPP), gross ecosystem productivity (GEP), ecosystem respiration (ER), and net ecosystem exchange (NEE); we used linear mixed-effects models to further determine the relative contributions of various factors to the N-induced changes in these parameters. Our results showed that the ANPP, GEP, ER, and NEE all exhibited nonlinear responses to increasing N additions. Further analysis demonstrated that the plant N:P ratio played a dominate role in shaping these C exchange processes. There was a positive relationship between the N-induced changes in ANPP (ΔANPP) and the plant N:P ratio (ΔN:P), whereas the ΔGEP, ΔER, and ΔNEE exhibited quadratic correlations with the ΔN:P. In contrast, soil temperature and moisture were only secondary predictors for the changes in ecosystem production and C fluxes along the N addition gradient. These findings highlight the importance of plant N:P ratio in regulating ecosystem C exchange, which is crucial for improving our understanding of C cycles under the scenarios of global N enrichment.