22 research outputs found
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Intercomparison of methods of coupling between convection and large-scale circulation. 2: comparison over non-uniform surface conditions
As part of an international intercomparison project, the weak temperature gradient (WTG) and damped gravity wave (DGW) methods are used to parameterize large-scale dynamics in a set of cloud-resolving models (CRMs) and single column models (SCMs). The WTG or DGW method is implemented using a configuration that couples a model to a reference state defined with profiles obtained from the same model in radiative-convective equilibrium. We investigated the sensitivity of each model to changes in SST, given a fixed reference state. We performed a systematic comparison of the WTG and DGW methods in different models, and a systematic comparison of the behavior of those models using the WTG method and the DGW method. The sensitivity to the SST depends on both the large-scale parameterization method and the choice of the cloud model. In general, SCMs display a wider range of behaviors than CRMs. All CRMs using either the WTG or DGW method show an increase of precipitation with SST, while SCMs show sensitivities which are not always monotonic. CRMs using either the WTG or DGW method show a similar relationship between mean precipitation rate and column-relative humidity, while SCMs exhibit a much wider range of behaviors. DGW simulations produce large-scale velocity profiles which are smoother and less top-heavy compared to those produced by the WTG simulations. These large-scale parameterization methods provide a useful tool to identify the impact of parameterization differences on model behavior in the presence of two-way feedback between convection and the large-scale circulation
Structure-Based Design of Novel Class II c-Met Inhibitors: 1. Identification of Pyrazolone-Based Derivatives
Deregulation of c-Met receptor tyrosine kinase activity
leads to
tumorigenesis and metastasis in animal models. More importantly, the
identification of activating mutations in c-Met, as well as <i>MET</i> gene amplification in human cancers, points to c-Met
as an important target for cancer therapy. We have previously described
two classes of c-Met kinase inhibitors (class I and class II) that
differ in their binding modes and selectivity profiles. The class
II inhibitors tend to have activities on multiple kinases. Knowledge
of the binding mode of these molecules in the c-Met protein led to
the design and evaluation of several new class II c-Met inhibitors
that utilize various 5-membered cyclic carboxamides to conformationally
restrain key pharmacophoric groups within the molecule. These investigations
resulted in the identification of a potent and novel class of pyrazolone
c-Met inhibitors with good in vivo activity
Robust direct effect of carbon dioxide on tropical circulation and regional precipitation
International audiencePredicting the response of tropical rainfall to climate change remains a challenge(1). Rising concentrations of carbon dioxide are expected to affect the hydrological cycle through increases in global mean temperature and the water vapour content of the atmosphere(2-4). However, regional precipitation changes also closely depend on the atmospheric circulation, which is expected to weaken in a warmer world(4-6). Here, we assess the effect of a rise in atmospheric carbon dioxide concentrations on tropical circulation and precipitation by analysing results from a suite of simulations from multiple state-of-the-art climate models, and an operational numerical weather prediction model. In a scenario in which humans continue to use fossil fuels unabated, about half the tropical circulation change projected by the end of the twenty-first century, and consequently a large fraction of the regional precipitation change, is independent of global surfacewarming. Instead, these robust circulation and precipitation changes are a consequence of the weaker net radiative cooling of the atmosphere associated with higher atmospheric carbon dioxide levels, which affects the strength of atmospheric vertical motions. This implies that geo-engineering schemes aimed at reducing global warming without removing carbon dioxide from the atmosphere would fail to fully mitigate precipitation changes in the tropics. Strategies that may help constrain rainfall projections are suggested
Structure-Based Design of Novel Class II c-Met Inhibitors: 2. SAR and Kinase Selectivity Profiles of the Pyrazolone Series
As part of our effort toward developing an effective
therapeutic agent for c-Met-dependent tumors, a pyrazolone-based class
II c-Met inhibitor, <i>N</i>-(4-((6,7-dimethoxyquinolin-4-yl)Âoxy)-3-fluorophenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1<i>H</i>-pyrazole-4-carboxamide (<b>1</b>), was identified.
Knowledge of the binding mode of this molecule in both c-Met and VEGFR-2
proteins led to a novel strategy for designing more selective analogues
of <b>1</b>. Along with detailed SAR information, we demonstrate
that the low kinase selectivity associated with class II c-Met inhibitors
can be improved significantly. This work resulted in the discovery
of potent c-Met inhibitors with improved selectivity profiles over
VEGFR-2 and IGF-1R that could serve as useful tools to probe the relationship
between kinase selectivity and in vivo efficacy in tumor xenograft
models. Compound <b>59e</b> (AMG 458) was ultimately advanced
into preclinical safety studies
Identification of (<i>R</i>)â<i>N</i>â((4-Methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-1-(1-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)ethyl)â1<i>H</i>âindole-3-carboxamide (CPI-1205), a Potent and Selective Inhibitor of Histone Methyltransferase EZH2, Suitable for Phase I Clinical Trials for BâCell Lymphomas
Polycomb
repressive complex 2 (PRC2) has been shown to play a major
role in transcriptional silencing in part by installing methylation
marks on lysine 27 of histone 3. Dysregulation of PRC2 function correlates
with certain malignancies and poor prognosis. EZH2 is the catalytic
engine of the PRC2 complex and thus represents a key candidate oncology
target for pharmacological intervention. Here we report the optimization
of our indole-based EZH2 inhibitor series that led to the identification
of CPI-1205, a highly potent (biochemical IC<sub>50</sub> = 0.002
ÎŒM, cellular EC<sub>50</sub> = 0.032 ÎŒM) and selective
inhibitor of EZH2. This compound demonstrates robust antitumor effects
in a Karpas-422 xenograft model when dosed at 160 mg/kg BID and is
currently in Phase I clinical trials. Additionally, we disclose the
co-crystal structure of our inhibitor series bound to the human PRC2
complex