Selecting optimal drug-intervention in a pathway involving receptor tyrosine kinases (RTKs). (May 2016)

• Record Type: Journal Article
• Authors: Benson, Neil; van der Graaf, Piet H.; Peletier, Lambertus A.
• Is Part Of: Nonlinear analysis. Volume 137(2016)
• Page Start: 148
• Page End: 170
• Publication Date: 2016-05
• Subjects: 34D15 -- 34E13 -- 92C42 -- 92C45; Receptors tyrosine kinases -- Systems pharmacology -- Singular perturbations; Mathematical analysis -- Periodicals; Functional analysis -- Periodicals; Nonlinear theories -- Periodicals; Analyse mathématique -- Périodiques; Analyse fonctionnelle -- Périodiques; Théories non linéaires -- Périodiques; Functional analysis; Mathematical analysis; Nonlinear theories; Periodicals; Electronic journals; 515.7248
• DOI: 10.1016/j.na.2015.12.009
• Languages: English
• ISSNs: 0362-546X

Abstract

Abstract: A recently developed system-pharmacological model for the dynamics of receptor tyrosine kinases is used to compare different targets for drug action: one aiming at binding endogenous ligand needed for phosphorylation and another binding receptors at their kinase domains and thus preventing them to generate phosphorylation. We obtain quantitative estimates for the effectivity of the inhibitor which demonstrate the influence of drug-properties such as dose, affinity to target and drug-elimination rates. Highlights: A system-pharmacological model has been developed for studying qualitatively and quantitatively cross-membrane signalling via RTK's. It has been shown that the physiological structure, which differentiates between the interstitial fluid and the cellular space, is critical in determining the efficacy of drugs. The efficacy of two different inhibitors, one targeting the top of the pathway (the ligand) and one targeting the bottom of the pathway (the receptor-kinase), has been compared quantitatively.