title: Translating slow-binding inhibition kinetics into cellular and in vivo effects.
abstract: 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 drug-target complex has a longer half-life than off-target-drug 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 drug-target 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.
authors.affiliation: Infection Innovative Medicines Unit, AstraZeneca Research and Development, Waltham, Massachusetts, USA.
authors.forename: Grant K
authors.initials: GK
authors.lastname: Walkup
authors.affiliation: Infection Innovative Medicines Unit, AstraZeneca Research and Development, Waltham, Massachusetts, USA.
authors.forename: Zhiping
authors.initials: Z
authors.lastname: You
authors.affiliation: Infection Innovative Medicines Unit, AstraZeneca Research and Development, Waltham, Massachusetts, USA.
authors.forename: Philip L
authors.initials: PL
authors.lastname: Ross
authors.affiliation: Institute for Chemical Biology and Drug Discovery, Department of Chemistry, Stony Brook University, Stony Brook, New York, USA.
authors.forename: Eleanor K H
authors.initials: EK
authors.lastname: Allen
authors.affiliation: Institute for Chemical Biology and Drug Discovery, Department of Chemistry, Stony Brook University, Stony Brook, New York, USA.
authors.forename: Fereidoon
authors.initials: F
authors.lastname: Daryaee
authors.affiliation: Infection Innovative Medicines Unit, AstraZeneca Research and Development, Waltham, Massachusetts, USA.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Hale
authors.affiliation: Infection Innovative Medicines Unit, AstraZeneca Research and Development, Waltham, Massachusetts, USA.
authors.forename: John
authors.initials: J
authors.lastname: O'Donnell
authors.affiliation: Infection Innovative Medicines Unit, AstraZeneca Research and Development, Waltham, Massachusetts, USA.
authors.forename: David E
authors.initials: DE
authors.lastname: Ehmann
authors.affiliation: Infection Innovative Medicines Unit, AstraZeneca Research and Development, Waltham, Massachusetts, USA.
authors.forename: Virna J A
authors.initials: VJ
authors.lastname: Schuck
authors.affiliation: Infection Innovative Medicines Unit, AstraZeneca Research and Development, Waltham, Massachusetts, USA.
authors.forename: Ed T
authors.initials: ET
authors.lastname: Buurman
authors.affiliation: Infection Innovative Medicines Unit, AstraZeneca Research and Development, Waltham, Massachusetts, USA.
authors.forename: Allison L
authors.initials: AL
authors.lastname: Choy
authors.affiliation: Infection Innovative Medicines Unit, AstraZeneca Research and Development, Waltham, Massachusetts, USA.
authors.forename: Laurel
authors.initials: L
authors.lastname: Hajec
authors.affiliation: Infection Innovative Medicines Unit, AstraZeneca Research and Development, Waltham, Massachusetts, USA.
authors.forename: Kerry
authors.initials: K
authors.lastname: Murphy-Benenato
authors.affiliation: Infection Innovative Medicines Unit, AstraZeneca Research and Development, Waltham, Massachusetts, USA.
authors.forename: Valerie
authors.initials: V
authors.lastname: Marone
authors.affiliation: Infection Innovative Medicines Unit, AstraZeneca Research and Development, Waltham, Massachusetts, USA.
authors.forename: Sara A
authors.initials: SA
authors.lastname: Patey
authors.affiliation: Infection Innovative Medicines Unit, AstraZeneca Research and Development, Waltham, Massachusetts, USA.
authors.forename: Lena A
authors.initials: LA
authors.lastname: Grosser
authors.affiliation: Infection Innovative Medicines Unit, AstraZeneca Research and Development, Waltham, Massachusetts, USA.
authors.forename: Michele
authors.initials: M
authors.lastname: Johnstone
authors.affiliation: Department of Oral Biology and Pathology, Stony Brook University, Stony Brook, New York, USA.
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Walker
authors.affiliation: Institute for Chemical Biology and Drug Discovery, Department of Chemistry, Stony Brook University, Stony Brook, New York, USA.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Tonge
authors.affiliation: Infection Innovative Medicines Unit, AstraZeneca Research and Development, Waltham, Massachusetts, USA.
authors.forename: Stewart L
authors.initials: SL
authors.lastname: Fisher
mesh_terms: D000581:Amidohydrolases / Q000037:antagonists & inhibitors*; D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D006877:Hydroxamic Acids / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D007700:Kinetics; D008815:Mice, Inbred Strains; D008826:Microbial Sensitivity Tests; D008954:Models, Biological; D015394:Molecular Structure; D011485:Protein Binding; D011550:Pseudomonas aeruginosa / Q000187:drug effects / Q000201:enzymology; D013912:Threonine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D013997:Time Factors
chemical_list: D000900:Anti-Bacterial Agents; C525369:CHIR 090; D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; D013912:Threonine; D000581:Amidohydrolases; C514484:LpxC deacetylase, Pseudomonas