36 research outputs found
Two additive mechanisms impair the differentiation of 'substrate-selective' p38 inhibitors from classical p38 inhibitors in vitro
<p>Abstract</p> <p>Background</p> <p>The success of anti-TNF biologics for the treatment of rheumatoid arthritis has highlighted the importance of understanding the intracellular pathways that regulate TNF production in the quest for an orally-available small molecule inhibitor. p38 is known to strongly regulate TNF production via MK2. The failure of several p38 inhibitors in the clinic suggests the importance of other downstream pathways in normal cell function. Recent work has described a 'substrate-selective' p38 inhibitor that is able to preferentially block the activity of p38 against one substrate (MK2) versus another (ATF2). Using a combined experimental and computational approach, we have examined this mechanism in greater detail for two p38 substrates, MK2 and ATF2.</p> <p>Results</p> <p>We found that in a dual (MK2 and ATF2) substrate assay, MK2-p38 interaction reduced the activity of p38 against ATF2. We further constructed a detailed kinetic mechanistic model of p38 phosphorylation in the presence of multiple substrates and successfully predicted the performance of classical and so-called 'substrate-selective' p38 inhibitors in the dual substrate assay. Importantly, it was found that excess MK2 results in a stoichiometric effect in which the formation of p38-MK2-inhibitor complex prevents the phosphorylation of ATF2, despite the preference of the compound for the p38-MK2 complex over the p38-ATF2 complex. MK2 and p38 protein expression levels were quantified in U937, Thp-1 and PBMCs and found that [MK2] > [p38].</p> <p>Conclusion</p> <p>Our integrated mechanistic modeling and experimental validation provides an example of how systems biology approaches can be applied to drug discovery and provide a basis for decision-making with limited chemical matter. We find that, given our current understanding, it is unlikely that 'substrate-selective' inhibitors of p38 will work as originally intended when placed in the context of more complex cellular environments, largely due to a stoichiometric excess of MK2 relative to p38.</p
The SUrvey for Pulsars and Extragalactic Radio Bursts â II. New FRB discoveries and their follow-up
We report the discovery of four Fast Radio Bursts (FRBs) in the ongoing SUrvey for Pulsars and Extragalactic Radio Bursts at the Parkes Radio Telescope: FRBs 150610, 151206, 151230 and 160102. Our real-time discoveries have enabled us to conduct extensive, rapid multimessenger follow-up at 12 major facilities sensitive to radio, optical, X-ray, gamma-ray photons and neutrinos on time-scales ranging from an hour to a few months post-burst. No counterparts to the FRBs were found and we provide upper limits on afterglow luminosities. None of the FRBs were seen to repeat. Formal fits to all FRBs show hints of scattering while their intrinsic widths are unresolved in time. FRB 151206 is at low Galactic latitude, FRB 151230 shows a sharp spectral cut-off, and FRB 160102 has the highest dispersion measure (DM = 2596.1 ± 0.3âpcâcmâ3) detected to date. Three of the FRBs have high dispersion measures (DM > 1500âpcâcmâ3), favouring a scenario where the DM is dominated by contributions from the intergalactic medium. The slope of the Parkes FRB source counts distribution with fluences >2âJyâms is α=â2.2+0.6â1.2 and still consistent with a Euclidean distribution (α = â3/2). We also find that the all-sky rate is 1.7+1.5â0.9Ă103 FRBs/(4Ï sr)/day above âŒ2Jyms and there is currently no strong evidence for a latitude-dependent FRB sky rate
Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease
Background: Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved. Methods: We conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1ÎČ, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. RESULTS: At 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in the 300-mg group than in the placebo group. Canakinumab did not reduce lipid levels from baseline. At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group. The hazard ratios as compared with placebo were as follows: in the 50-mg group, 0.93 (95% confidence interval [CI], 0.80 to 1.07; P = 0.30); in the 150-mg group, 0.85 (95% CI, 0.74 to 0.98; P = 0.021); and in the 300-mg group, 0.86 (95% CI, 0.75 to 0.99; P = 0.031). The 150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included hospitalization for unstable angina that led to urgent revascularization (hazard ratio vs. placebo, 0.83; 95% CI, 0.73 to 0.95; P = 0.005). Canakinumab was associated with a higher incidence of fatal infection than was placebo. There was no significant difference in all-cause mortality (hazard ratio for all canakinumab doses vs. placebo, 0.94; 95% CI, 0.83 to 1.06; P = 0.31). Conclusions: Antiinflammatory therapy targeting the interleukin-1ÎČ innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering. (Funded by Novartis; CANTOS ClinicalTrials.gov number, NCT01327846.
Multi-messenger observations of a binary neutron star merger
On 2017 August 17 a binary neutron star coalescence candidate (later designated GW170817) with merger time 12:41:04 UTC was observed through gravitational waves by the Advanced LIGO and Advanced Virgo detectors. The Fermi Gamma-ray Burst Monitor independently detected a gamma-ray burst (GRB 170817A) with a time delay of ~1.7 s with respect to the merger time. From the gravitational-wave signal, the source was initially localized to a sky region of 31 deg2 at a luminosity distance of 40+8-8 Mpc and with component masses consistent with neutron stars. The component masses were later measured to be in the range 0.86 to 2.26 Mo. An extensive observing campaign was launched across the electromagnetic spectrum leading to the discovery of a bright optical transient (SSS17a, now with the IAU identification of AT 2017gfo) in NGC 4993 (at ~40 Mpc) less than 11 hours after the merger by the One- Meter, Two Hemisphere (1M2H) team using the 1 m Swope Telescope. The optical transient was independently detected by multiple teams within an hour. Subsequent observations targeted the object and its environment. Early ultraviolet observations revealed a blue transient that faded within 48 hours. Optical and infrared observations showed a redward evolution over ~10 days. Following early non-detections, X-ray and radio emission were discovered at the transientâs position ~9 and ~16 days, respectively, after the merger. Both the X-ray and radio emission likely arise from a physical process that is distinct from the one that generates the UV/optical/near-infrared emission. No ultra-high-energy gamma-rays and no neutrino candidates consistent with the source were found in follow-up searches. These observations support the hypothesis that GW170817 was produced by the merger of two neutron stars in NGC4993 followed by a short gamma-ray burst (GRB 170817A) and a kilonova/macronova powered by the radioactive decay of r-process nuclei synthesized in the ejecta
Distributed Drug Discovery, Part 1: Linking Academia and Combinatorial Chemistry to Find Drug Leads for Developing World Diseases
Multi-messenger Observations of a Binary Neutron Star Merger
On 2017 August 17 a binary neutron star coalescence candidate (later
designated GW170817) with merger time 12:41:04 UTC was observed through
gravitational waves by the Advanced LIGO and Advanced Virgo detectors.
The Fermi Gamma-ray Burst Monitor independently detected a gamma-ray
burst (GRB 170817A) with a time delay of ⌠1.7 {{s}} with respect to
the merger time. From the gravitational-wave signal, the source was
initially localized to a sky region of 31 deg2 at a
luminosity distance of {40}-8+8 Mpc and with
component masses consistent with neutron stars. The component masses
were later measured to be in the range 0.86 to 2.26 {M}ÈŻ
. An extensive observing campaign was launched across the
electromagnetic spectrum leading to the discovery of a bright optical
transient (SSS17a, now with the IAU identification of AT 2017gfo) in NGC
4993 (at ⌠40 {{Mpc}}) less than 11 hours after the merger by the
One-Meter, Two Hemisphere (1M2H) team using the 1 m Swope Telescope. The
optical transient was independently detected by multiple teams within an
hour. Subsequent observations targeted the object and its environment.
Early ultraviolet observations revealed a blue transient that faded
within 48 hours. Optical and infrared observations showed a redward
evolution over âŒ10 days. Following early non-detections, X-ray and
radio emission were discovered at the transientâs position ⌠9
and ⌠16 days, respectively, after the merger. Both the X-ray and
radio emission likely arise from a physical process that is distinct
from the one that generates the UV/optical/near-infrared emission. No
ultra-high-energy gamma-rays and no neutrino candidates consistent with
the source were found in follow-up searches. These observations support
the hypothesis that GW170817 was produced by the merger of two neutron
stars in NGC 4993 followed by a short gamma-ray burst (GRB 170817A) and
a kilonova/macronova powered by the radioactive decay of r-process
nuclei synthesized in the ejecta.</p
Supp_Material_for_Nuisance_Compounds_PAINS_Filters__by_Chakravorty_et_al â Supplemental material for Nuisance Compounds, PAINS Filters, and Dark Chemical Matter in the GSK HTS Collection
<p>Supplemental material, Supp_Material_for_Nuisance_Compounds_PAINS_Filters__by_Chakravorty_et_al for Nuisance Compounds, PAINS Filters, and Dark Chemical Matter in the GSK HTS Collection by Subhas J. Chakravorty, James Chan, Marie Nicole Greenwood, Ioana Popa-Burke, Katja S. Remlinger, Stephen D. Pickett, Darren V. S. Green, Martin C. Fillmore, Tony W. Dean, Juan I. Luengo and Ricardo MacarrĂłn in SLAS Discovery</p
Supp_Table_3S_Nuisance_Compounds_PAINS_filters__Chakravorty_et_al â Supplemental material for Nuisance Compounds, PAINS Filters, and Dark Chemical Matter in the GSK HTS Collection
<p>Supplemental material, Supp_Table_3S_Nuisance_Compounds_PAINS_filters__Chakravorty_et_al for Nuisance Compounds, PAINS Filters, and Dark Chemical Matter in the GSK HTS Collection by Subhas J. Chakravorty, James Chan, Marie Nicole Greenwood, Ioana Popa-Burke, Katja S. Remlinger, Stephen D. Pickett, Darren V. S. Green, Martin C. Fillmore, Tony W. Dean, Juan I. Luengo and Ricardo MacarrĂłn in SLAS Discovery</p