Prolonged and tunable residence time using reversible covalent kinase inhibitors.

Drugs with prolonged on-target residence times often show superior efficacy, yet general strategies for optimizing drug-target residence time are lacking. Here we made progress toward this elusive goal by targeting a noncatalytic cysteine in Bruton's tyrosine kinase (BTK) with reversible covalent inhibitors. Using an inverted orientation of the cysteine-reactive cyanoacrylamide electrophile, we identified potent and selective BTK inhibitors that demonstrated biochemical residence times spanning from minutes to 7 d. An inverted cyanoacrylamide with prolonged residence time in vivo remained bound to BTK for more than 18 h after clearance from the circulation. The inverted cyanoacrylamide strategy was further used to discover fibroblast growth factor receptor (FGFR) kinase inhibitors with residence times of several days, demonstrating the generalizability of the approach. Targeting of noncatalytic cysteines with inverted cyanoacrylamides may serve as a broadly applicable platform that facilitates 'residence time by design', the ability to modulate and improve the duration of target engagement in vivo

Soft solar X-rays and solar activity

Minor Hα activity, consisting of small brightenings and small, surgelike spikes, was observed to take place above an active center at the solar limb in good time-association with small fluctuations in the soft X-ray background flux, suggesting that even small dynamical events seen optically are associated with coronal heating. The ratio of Hα flux to soft X-ray flux in some of the surges was approximately the same as the ratio already established for flares. The total energy dissipated by the events in a 24-hour period is estimated; it is approximately equivalent to that released by one flare of imp 1 per day.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/43719/1/11207_2004_Article_BF00155785.pd

Abstracts from the NIHR INVOLVE Conference 2017

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