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SUMMARY:Improving the Prediction of In vivo Drug Activity - Peter Tonge\, 
 Institute for Chemical Biology & Drug Discovery\, Stony Brook University U
 SA
DTSTART:20180116T160000Z
DTEND:20180116T170000Z
UID:TALK98365@talks.cam.ac.uk
CONTACT:Alice Wood
DESCRIPTION:Time-dependent enzyme inhibitors are of particular interest in
  drug discovery programs since the rate of complex dissociation (koff) can
  be slower than the time scale of in vivo drug metabolism and elimination\
 , leading to sustained target occupancy\, and thus enabling dosing frequen
 cy and exposure to be reduced. We have developed a mechanistic PK/PD model
  that enables the kinetic parameters for time-dependent target engagement 
 to be used to predict in vivo drug efficacy. To inform and interrogate the
  PK/PD model\, we are developing compounds with altered residence times on
  their targets and quantifying the molecular factors that modulate the cou
 pling of time- dependent enzyme inhibition to prolonged drug activity foll
 owing compound washout. This analysis provides direct insight into target 
 vulnerability. Data on three systems will be discussed including reversibl
 e inhibitors of two antibacterial targets\, and a covalent inhibitor of Br
 uton’s tyrosine kinase (Btk)\, a target for treating diseases stemming f
 rom B cell dysregulation. The ability to accurately quantify target engage
 ment as a function of time and drug concentration is expected to dramatica
 lly improve the prediction of in vivo drug activity across all therapeutic
  areas. http://pubs.acs.org/doi/pdf/10.1021/acschemneuro.7b00185
LOCATION:Wolfson Lecture Theatre
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