Predicting drug efficacy in humans remains a major barrier to the development of novel therapeutics. We propose that the kinetics of drug-target interactions, and in particular the life-time of the drug-target complex (residence time), should be included in predictions of drug activity, since drug and target are not at equilibrium in vivo. To inform the development of mechanistic PK/PD models that incorporate drug-target kinetics, we are quantifying the molecular factors that modulate the coupling of drug-target residence time to prolonged drug activity following compound washout. This analysis provides direct insight into target vulnerability. Data on three systems will be discussed: reversible inhibitors of two antibacterial targets, the enoyl-ACP reductase from Staphylococcus aureus, and the LpxC enzyme from Pseudomonas aeruginosa, and a covalent inhibitor of Bruton’s tyrosine kinase (Btk), a target for treating diseases stemming from B cell dysregulation.

Linking target engagement and in vivo drug activity: Insights into target vulnerability

253rd National Meeting (2017)

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