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 frequency 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 coupling of time-dependent enzyme inhibition 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 Mycobacterium tuberculosis, and the LpxC enzyme from Pseudomonas aeruginosa, and covalent inhibitors of Bruton’s tyrosine kinase (Btk), a target for treating diseases stemming from B cell dysregulation. Translational activities include the use of X-ray crystallography and MD simulations to determine the molecular basis for residence time and guide inhibitor discovery, quantification of protein turnover at the whole cell level, determination of drug biodistribution using non-invasive PET imaging, and predictions of in vivo drug activity in animal models of disease.

Modulating drug-target residence time, assessing target vulnerability, and predicting in vivo drug activity

254th National Meeting (2017)

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