Probing the Inner Jet of the Quasar PKS 1510-089 with Multi-waveband Monitoring during Strong Gamma-ray Activity

We present results from monitoring the multi-waveband flux, linear polarization, and parsec-scale structure of the quasar PKS 1510-089, concentrating on eight major gamma-ray flares that occurred during the interval 2009.0-2009.5. The gamma-ray peaks were essentially simultaneous with maxima at optical wavelengths, although the flux ratio of the two wavebands varied by an order of magnitude. The optical polarization vector rotated by 720 degrees during a 5-day period encompassing six of these flares. This culminated in a very bright, roughly 1 day, optical and gamma-ray flare as a bright knot of emission passed through the highest-intensity, stationary feature (the "core") seen in 43 GHz Very Long Baseline Array images. The knot continued to propagate down the jet at an apparent speed of 22c and emit strongly at gamma-ray energies as a months-long X-ray/radio outburst intensified. We interpret these events as the result of the knot following a spiral path through a mainly toroidal magnetic field pattern in the acceleration and collimation zone of the jet, after which it passes through a standing shock in the 43 GHz core and then continues downstream. In this picture, the rapid gamma-ray flares result from scattering of infrared seed photons from a relatively slow sheath of the jet as well as from optical synchrotron radiation in the faster spine. The 2006-2009.7 radio and X-ray flux variations are correlated at very high significance; we conclude that the X-rays are mainly from inverse Compton scattering of infrared seed photons by 20-40 MeV electrons.Comment: 10 pages of text + 5 figures, to be published in Astrophysical Journal Letters in 201

Flaring Behavior of the Quasar 3C~454.3 across the Electromagnetic Spectrum

We analyze the behavior of the parsec-scale jet of the quasar 3C~454.3 during pronounced flaring activity in 2005-2008. Three major disturbances propagated down the jet along different trajectories with Lorentz factors $\Gamma>$10. The disturbances show a clear connection with millimeter-wave outbursts, in 2005 May/June, 2007 July, and 2007 December. High-amplitude optical events in the $R$-band light curve precede peaks of the millimeter-wave outbursts by 15-50 days. Each optical outburst is accompanied by an increase in X-ray activity. We associate the optical outbursts with propagation of the superluminal knots and derive the location of sites of energy dissipation in the form of radiation. The most prominent and long-lasting of these, in 2005 May, occurred closer to the black hole, while the outbursts with a shorter duration in 2005 Autumn and in 2007 might be connected with the passage of a disturbance through the millimeter-wave core of the jet. The optical outbursts, which coincide with the passage of superluminal radio knots through the core, are accompanied by systematic rotation of the position angle of optical linear polarization. Such rotation appears to be a common feature during the early stages of flares in blazars. We find correlations between optical variations and those at X-ray and $\gamma$-ray energies. We conclude that the emergence of a superluminal knot from the core yields a series of optical and high-energy outbursts, and that the mm-wave core lies at the end of the jet's acceleration and collimation zone.Comment: 57 pages, 23 figures, 8 tables (submitted to ApJ

Multiparameter Lead Optimization to Give an Oral Checkpoint Kinase 1 (CHK1) Inhibitor Clinical Candidate: (R)-5-((4-((Morpholin-2-ylmethyl)amino)-5-(trifluoromethyl)pyridin-2-yl)amino)pyrazine-2-carbonitrile (CCT245737)

Multiparameter optimization of a series of 5-((4-aminopyridin-2-yl)amino)pyrazine-2-carbonitriles resulted in the identification of a potent and selective oral CHK1 preclinical development candidate with in vivo efficacy as a potentiator of deoxyribonucleic acid (DNA) damaging chemotherapy and as a single agent. Cellular mechanism of action assays were used to give an integrated assessment of compound selectivity during optimization resulting in a highly CHK1 selective adenosine triphosphate (ATP) competitive inhibitor. A single substituent vector directed away from the CHK1 kinase active site was unexpectedly found to drive the selective cellular efficacy of the compounds. Both CHK1 potency and off-target human ether-a-go-go-related gene (hERG) ion channel inhibition were dependent on lipophilicity and basicity in this series. Optimization of CHK1 cellular potency and in vivo pharmacokinetic–pharmacodynamic (PK–PD) properties gave a compound with low predicted doses and exposures in humans which mitigated the residual weak in vitro hERG inhibition

Design and evaluation of 3,6-di(hetero)aryl imidazo[1,2-a]pyrazines as inhibitors of checkpoint and other kinases

A range of 3,6-di(hetero)arylimidazo[1,2-a]pyrazine ATP-competitive inhibitors of CHK1 were developed by scaffold hopping from a weakly active screening hit. Efficient synthetic routes for parallel synthesis were developed to prepare analogues with improved potency and ligand efficiency against CHK1. Kinase profiling showed that the imidazo[1,2-a]pyrazines could inhibit other kinases, including CHK2 and ABL, with equivalent or better potency depending on the pendant substitution. These 3,6-di(hetero)aryl imidazo[1,2-a]pyrazines appear to represent a general kinase inhibitor scaffold

Correlation Analysis of Delays between Variations of Gamma-Ray and Optical Light Curves of Blazars

We have been performing multi-wavelength monitoring of a sample of γ -ray blazars since the launch of the Fermi Gamma-ray Space Telescope in 2008. We present γ -ray and optical light curves for several quasars and BL Lac objects from the sample to illustrate different patterns of variability. We investigate correlations between γ -ray and R-band light curves and, if these are statistically significant, determine delays between variations at the two wavebands. Such time delays can reveal the relative locations of the emitting regions in AGN jets and the origin of the high-energy photons. We present preliminary results of this analysis. Of the 29 blazars with sufficient time coverage, 17 display a significant, singular, correlated time lag when tested over the entire 7-year period. Of these sources, the six that exhibit a consistent time lag across a majority of epochs of high activity have lags of 0 ± 7 days; the 11 without consistency across epochs of high activity generally display longer mean lags, with γ -ray leading optical. Eleven sources display no significant singular correlation over either the entire 7-year period or across shorter intervals. No significant difference is apparent between the BL Lac objects and FSRQs. Even after 7 years of monitoring, our correlation analysis remains plagued with uncertainties due to insufficient data

The connection between the parsec-scale radio jet and gamma-ray flares in the blazar 1156+295

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