Translating slow-binding inhibition kinetics into cellular and in vivo effects

Walkup, Grant K.; You, Zhiping; Ross, Philip L.; Allen, Eleanor K. H.; Daryaee, Fereidoon; Hale, Michael R.; O‘Donnell, John C.; Ehmann, David E.; Schuck, Virna; Buurman, Ed T.; Choy, Allison L.; Hajec, Laurel I.; Murphy-Benenato, Kerry E.; Marone, Valerie; Patey, Sara A.; Grosser, Lena A; Johnstone, Michele; Walker, Stephen G.; Tonge, Peter J.; Fisher, Stewart L.

doi:10.1038/nchembio.1796

Cited by 134 publications

(214 citation statements)

References 55 publications

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“…However, a long residence time may also trigger 'mechanism'-based toxicity, such as the emergence of the extrapyramidal side effects associated with antipsychotic agents such as haloperidol [10]. These side effects are greatly reduced with fast-dissociating 'atypical' antipsychotic agents such as clozapine because their D 2 receptor blockade can be overcome/surmounted effectively by brief increases in the dopamine concentration in the striatum [11].There is increasing concern that integrating the 'residence time' concept in the drug discovery cascade may have only limited translatability into clinical efficacy [12,13]. In support of this view, it has been suggested [14] that many therapeutic drugs have slower elimination than dissociation rates, indicating that the PK component prevails.…”

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confidence: 99%

Cell membranes… and how long drugs may exert beneficial pharmacological activity in vivo

Vauquelin

2016

Brit J Clinical Pharma

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The time course of the beneficial pharmacological effect of a drug has long been considered to depend merely on the temporal fluctuation of its free concentration. Only in the last decade has it become widely accepted that target-binding kinetics can also affect in vivo pharmacological activity. Although current reviews still essentially focus on genuine dissociation rates, evidence is accumulating that additional micro-pharmacokinetic (PK) and -pharmacodynamic (PD) mechanisms, in which the cell membrane plays a central role, may also increase the residence time of a drug on its target. The present review provides a compilation of otherwise widely dispersed information on this topic. The cell membrane can intervene in drug binding via the following three major mechanisms: (i) by acting as a sink/repository for the drug; (ii) by modulating the conformation of the drug and even by participating in the binding process; and (iii) by facilitating the approach (and rebinding) of the drug to the target. To highlight these mechanisms, we focus on drugs that are currently used in clinical therapy, such as the antihypertensive angiotensin II type 1 receptor antagonist candesartan, the atypical antipsychotic agent clozapine and the bronchodilator salmeterol. Although the role of cell membranes in PK-PD modelling is gaining increasing interest, many issues remain unresolved. It is likely that novel biophysical and computational approaches will provide improved insights in the near future. IntroductionThe pharmacokinetic (PK) and pharmacodynamic (PD) properties of a drug are determinants of its efficacy and the duration of its clinical action [1]. PK and PD have long been considered to be separate disciplines, and the time course of the pharmacological effect of a drug has essentially been considered in terms of the temporal fluctuation of its free concentration [2]. In accordance with this principle, the frequently observed time lag between the concentration of a drug in the systemic circulation and its effect was initially attributed to slow equilibration between the plasma and a hypothetical target-surrounding 'effect compartment' [3]. By contrast, preclinical screening studies traditionally aim to optimize drug candidates in terms of only their efficacy and potency (i.e. PD properties). Inherent to this practice is the proposal that drug-target interactions are adequately described by equilibrium equations and, hence, that association and dissociation rates play only subordinate roles. In addition to a few noteworthy exceptions [4,5], it is only in the last decade that it has become fashionable to include binding kinetics as an additional criterion for clinical efficacy. This insight was largely sparked by the seminal articles by Swinney [6] and Copeland et al. [7]. The numerous review articles that have been published subsequently have focused mainly on long residence times. This property is now recognized to play a key role with respect to the clinical British Journal of Clinical Pharmacology Br J Clin Pharmacol (2016...

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confidence: 99%

Cell membranes… and how long drugs may exert beneficial pharmacological activity in vivo

Vauquelin

2016

Brit J Clinical Pharma

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“…An example of this is reflected in the development of Martinostat, an 11 C-labeled hydroxamate PET radiotracer that targets histone deacetylase in tumor cells. An underlying theme of this work is that extensive structure-activity relationship analyses are required to identify a brain-penetrant imaging agent and the translational value of a molecular imaging agent.…”

Section: Imaging Of Drugs and Drug Effects In The Cnsmentioning

confidence: 99%

“…A long residence time correlates with increased target engagement at low drug concentration, in principal enabling drugs to be dosed less frequently, thereby improving safety. Pharmacokinetic (PK)/pharmacodynamic (PD) models that incorporate drug-target kinetics can best predict clinical effect as most standard approaches assume rapid equilibrium between drug and target despite the nonequilibrated environment in the human body [10,11]. This approach sheds light on target vulnerability, the proportion of the target that needs to be inhibited to impact cell growth or survival.…”

Section: Clinical Reality and Pharmaceutical Challengesmentioning

confidence: 99%

CNS Anticancer Drug Discovery and Development: 2016 conference insights

Levin

Abrey

Heffron³

et al. 2017

CNS Oncol.

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The 2016 second CNS Anticancer Drug Discovery and Development Conference addressed diverse viewpoints about why new drug discovery/development focused on CNS cancers has been sorely lacking. Despite more than 70,000 individuals in the USA being diagnosed with a primary brain malignancy and 151,669-286,486 suffering from metastatic CNS cancer, in 1999, temozolomide was the last drug approved by the US FDA as an anticancer agent for high-grade gliomas. Among the topics discussed were economic factors and pharmaceutical risk assessments, regulatory constraints and perceptions and the need for improved imaging surrogates of drug activity. Included were modeling tumor growth and drug effects in a medical environment in which direct tumor sampling for biological effects can be problematic, potential new drugs under investigation and targets for drug discovery and development. The long trajectory and diverse impediments to novel drug discovery, and expectation that more than one drug will be needed to adequately inhibit critical intracellular tumor pathways were viewed as major disincentives for most pharmaceutical/ biotechnology companies. While there were a few unanimities, one consensus is the need for continued and focused discussion among academic and industry scientists and clinicians to address tumor targets, new drug chemistry, and more time-and cost-efficient clinical trials based on surrogate end points.

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“…In another recent study, Walkup et al described a mechanistic pharmacodynamics (PD) model that includes drug-target kinetic parameters. 7 This model predicted timedependent antibacterial activity for inhibitors of LpxC, a zinc metalloenzyme involved in the biosynthesis of cell wall lipopolysaccharides from Pseudomonas aeruginosa in intact cells and in an animal model of infection. This study represents a prospective example that integrates ligand−receptor BK to predict drug efficacy.…”

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confidence: 99%

“…Approaches that utilize prolonged occupancy of the drug on the designated target while minimizing binding to off-target proteins may improve a drug candidate's therapeutic index and thus yield compounds with desired kinetic selectivity. 7 One recent example toward this purpose comes from our own lab, where both equilibrium-and kinetic-based measurements were undertaken to examine the selectivity of a number of compounds for three adenosine receptor (A 1 AR, A 2A AR, and A 3 AR) subtypes. As a result, XAC and LUF5964, two AR antagonists, were kinetically more selective for the adenosine A 1 AR or A 3 AR, respectively, although they were nonselective in terms of their affinity.…”

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confidence: 99%

The Added Value of Assessing Ligand–Receptor Binding Kinetics in Drug Discovery

Guo

Heitman

IJzerman

2016

ACS Med. Chem. Lett.

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In the past decade drug research community has started to appreciate the indispensable role of ligand−receptor binding kinetics (BK) in drug discovery. Next to the classical equilibrium-based drug evaluation process with affinity and potency values as outcomes, kinetic investigation of the ligand−receptor interaction can aid compound triage in the hit-to-lead campaign and provide additional information to understand the molecular mechanism of drug action. Translational models incorporating BK are emerging as well, which represent powerful tools for the prediction of in vivo effects. In this viewpoint we will summarize some recent findings and discuss and emphasize the added value of ligand−receptor binding kinetics in drug research.

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Translating slow-binding inhibition kinetics into cellular and in vivo effects

Cited by 134 publications

References 55 publications

Cell membranes… and how long drugs may exert beneficial pharmacological activity in vivo

Cell membranes… and how long drugs may exert beneficial pharmacological activity in vivo

CNS Anticancer Drug Discovery and Development: 2016 conference insights

The Added Value of Assessing Ligand–Receptor Binding Kinetics in Drug Discovery

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