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PUBLISHED ONLINE: 20 APRIL 2015 | http://www.nature.com/doifinder/10.1038/nchembio.1796
Web End =DOI: 10.1038/NCHEMBIO.1796
Translating slow-binding inhibition kinetics into cellular and in vivo effects
Grant K Walkup1,4, Zhiping You1,5, Philip L Ross1,5, Eleanor K H Allen2,5, Fereidoon Daryaee2,
Michael R Hale1, John ODonnell1, David E Ehmann1, Virna J A Schuck1, Ed T Buurman1,
Allison L Choy1, Laurel Hajec1, Kerry Murphy-Benenato1, Valerie Marone1, Sara A Patey1, Lena A Grosser1, Michele Johnstone1, Stephen G Walker3, Peter J Tonge2* & Stewart L Fisher1*
Many drug candidates fail in clinical trials owing to a lack of efficacy from limited target engagement or an insufficient therapeutic index. Minimizing off-target effects while retaining the desired pharmacodynamic (PD) response can be achieved by reduced exposure for drugs that display kinetic selectivity in which the drugtarget complex has a longer half-life than off-targetdrug complexes. However, though slow-binding inhibition kinetics are a key feature of many marketed drugs, prospective tools that integrate drug-target residence time into predictions of drug efficacy are lacking, hindering the integration of drug-target kinetics into the drug discovery cascade. Here we describe a mechanistic PD model that includes drug-target kinetic parameters, including the on- and off-rates for the formation and breakdown of the drugtarget complex. We demonstrate the utility of this model by using it to predict dose response curves for inhibitors of the LpxC enzyme from Pseudomonas aeruginosa in an animal model of infection.
npg 201 5 Nature America, Inc. All rights reserved.
The majority of drug candidates fail in human clinical trials owing to a lack of efficacy or an insufficient therapeutic index, often as a result of limited target engagement or concomitant
drug binding to off-target receptors1,2. Currently, these critical drug parameters are not routinely fully evaluated until late stages of drug discovery. Developing a fundamental understanding of the pharmacokinetic (PK) and PD principles that govern drug action throughout the drug discovery process has been proposed as a mechanism for improving the success rate of new drug approvals2,3.
Recently, approaches that use prolonged occupancy of the drug on the designated target while minimizing binding to off-target proteins (kinetic selectivity) have been identified as particularly promising strategies for improving a drug candidate therapeutic index. Indeed, many marketed drugs dissociate slowly from their targets, emphasizing the potential importance of the drugtarget...