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Direct Measurement of Intracellular Compound Concentration by RapidFire Mass Spectrometry Offers Insights into Cell Permeability
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- Gordon, Laurie J (author)
- GlaxoSmithKline, Dept Biol Sci, Mol Discovery Res, Stevenage SG1 2NY, Herts, England
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- Allen, Morven (author)
- GlaxoSmithKline, Dept Biol Sci, Mol Discovery Res, Stevenage SG1 2NY, Herts, England
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- Artursson, Per (author)
- Uppsala universitet,Institutionen för farmaci
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- (creator_code:org_t)
- Elsevier BV, 2016
- 2016
- English.
- In: Journal of Biomolecular Screening. - : Elsevier BV. - 1087-0571 .- 1552-454X. ; 21:2, s. 156-164
- Journal article (peer-reviewed)
Abstract
Subject headings
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- One of the key challenges facing early stage drug discovery is understanding the commonly observed difference between the activity of compounds in biochemical assays and cellular assays. Traditionally, indirect or estimated cell permeability measurements such as estimations from logP or artificial membrane permeability are used to explain the differences. The missing link is a direct measurement of intracellular compound concentration in whole cells. This can, in some circumstances, be estimated from the cellular activity, but this may also be problematic if cellular activity is weak or absent. Advances in sensitivity and throughput of analytical techniques have enabled us to develop a high-throughput assay for the measurement of intracellular compound concentration for routine use to support lead optimization. The assay uses a RapidFire-MS based readout of compound concentration in HeLa cells following incubation of cells with test compound. The initial assay validation was performed by ultra-high performance liquid chromatography tandem mass spectrometry, and the assay was subsequently transferred to RapidFire tandem mass spectrometry. Further miniaturization and optimization were performed to streamline the process, increase sample throughput, and reduce cycle time. This optimization has delivered a semi-automated platform with the potential of production scale compound profiling up to 100 compounds per day.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Farmaceutiska vetenskaper (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Pharmaceutical Sciences (hsv//eng)
Keyword
- intracellular drug concentrations
- RapidFire-MS
- cell penetration
- drug accumulation
Publication and Content Type
- ref (subject category)
- art (subject category)
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- Gordon, Laurie J
- Allen, Morven
- Artursson, Per
- Hann, Michael M.
- Leavens, Bill J.
- Mateus, André
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- Readshaw, Simon
- Valko, Klara
- Wayne, Gareth J.
- West, Andy
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- About the subject
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- MEDICAL AND HEALTH SCIENCES
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- Uppsala University
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