Screening a protein kinase inhibitor library against Plasmodium falciparum

Irene Hallyburton, Raffaella Grimaldi, Andrew Woodland, Beatriz Baragana, Torsten Luksch, Daniel Spinks, Daniel James, Didier Leroy, David Waterson, Alan H. Fairlamb, Paul G. Wyatt, Ian H. Gilbert (Lead / Corresponding author), Julie A. Frearson

Research output: Contribution to journalArticle

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Abstract

Background: Protein kinases have been shown to be key drug targets, especially in the area of oncology. It is of interested to explore the possibilities of protein kinases as a potential target class in Plasmodium spp., the causative agents of malaria. However, protein kinase biology in malaria is still being investigated. Therefore, rather than assaying against individual protein kinases, a library of 4,731 compounds with protein kinase inhibitor-like scaffolds was screened against the causative parasite, Plasmodium falciparum. This approach is more holistic and considers the whole kinome, making it possible to identify compounds that inhibit more than one P. falciparum protein kinase, or indeed other malaria targets.

Results: As a result of this screen, 9 active compound series were identified; further validation was carried out on 4 of these series, with 3 being progressed into hits to lead chemistry. The detailed evaluation of one of these series is described.

Discussion: This screening approach proved to be an effective way to identify series for further optimisation against malaria. Compound optimisation was carried out in the absence of knowledge of the molecular target. Some of the series had to be halted for various reasons. Mode of action studies to find the molecular target may be useful when problems prevent further chemical optimisation.

Conclusions: Progressible series were identified through phenotypic screening of a relatively small focused kinase scaffold chemical library.
Original languageEnglish
Article number446
Pages (from-to)1-11
Number of pages11
JournalMalaria Journal
Volume16
DOIs
Publication statusPublished - 7 Nov 2017

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Plasmodium falciparum
Protein Kinase Inhibitors
Protein Kinases
Malaria
Small Molecule Libraries
Plasmodium
Parasites
Phosphotransferases
Pharmaceutical Preparations

Cite this

Hallyburton, Irene ; Grimaldi, Raffaella ; Woodland, Andrew ; Baragana, Beatriz ; Luksch, Torsten ; Spinks, Daniel ; James, Daniel ; Leroy, Didier ; Waterson, David ; Fairlamb, Alan H. ; Wyatt, Paul G. ; Gilbert, Ian H. ; Frearson, Julie A. / Screening a protein kinase inhibitor library against Plasmodium falciparum. In: Malaria Journal. 2017 ; Vol. 16. pp. 1-11.
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title = "Screening a protein kinase inhibitor library against Plasmodium falciparum",
abstract = "Background: Protein kinases have been shown to be key drug targets, especially in the area of oncology. It is of interested to explore the possibilities of protein kinases as a potential target class in Plasmodium spp., the causative agents of malaria. However, protein kinase biology in malaria is still being investigated. Therefore, rather than assaying against individual protein kinases, a library of 4,731 compounds with protein kinase inhibitor-like scaffolds was screened against the causative parasite, Plasmodium falciparum. This approach is more holistic and considers the whole kinome, making it possible to identify compounds that inhibit more than one P. falciparum protein kinase, or indeed other malaria targets.Results: As a result of this screen, 9 active compound series were identified; further validation was carried out on 4 of these series, with 3 being progressed into hits to lead chemistry. The detailed evaluation of one of these series is described.Discussion: This screening approach proved to be an effective way to identify series for further optimisation against malaria. Compound optimisation was carried out in the absence of knowledge of the molecular target. Some of the series had to be halted for various reasons. Mode of action studies to find the molecular target may be useful when problems prevent further chemical optimisation.Conclusions: Progressible series were identified through phenotypic screening of a relatively small focused kinase scaffold chemical library.",
author = "Irene Hallyburton and Raffaella Grimaldi and Andrew Woodland and Beatriz Baragana and Torsten Luksch and Daniel Spinks and Daniel James and Didier Leroy and David Waterson and Fairlamb, {Alan H.} and Wyatt, {Paul G.} and Gilbert, {Ian H.} and Frearson, {Julie A.}",
note = "This project was funded primarily by Medicines for Malaria Venture. We also like to acknowledge The Wellcome Trust for funding (Grant No.083481).",
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Hallyburton, I, Grimaldi, R, Woodland, A, Baragana, B, Luksch, T, Spinks, D, James, D, Leroy, D, Waterson, D, Fairlamb, AH, Wyatt, PG, Gilbert, IH & Frearson, JA 2017, 'Screening a protein kinase inhibitor library against Plasmodium falciparum', Malaria Journal, vol. 16, 446, pp. 1-11. https://doi.org/10.1186/s12936-017-2085-4

Screening a protein kinase inhibitor library against Plasmodium falciparum. / Hallyburton, Irene; Grimaldi, Raffaella; Woodland, Andrew; Baragana, Beatriz; Luksch, Torsten; Spinks, Daniel; James, Daniel; Leroy, Didier; Waterson, David; Fairlamb, Alan H.; Wyatt, Paul G.; Gilbert, Ian H. (Lead / Corresponding author); Frearson, Julie A.

In: Malaria Journal, Vol. 16, 446, 07.11.2017, p. 1-11.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Screening a protein kinase inhibitor library against Plasmodium falciparum

AU - Hallyburton, Irene

AU - Grimaldi, Raffaella

AU - Woodland, Andrew

AU - Baragana, Beatriz

AU - Luksch, Torsten

AU - Spinks, Daniel

AU - James, Daniel

AU - Leroy, Didier

AU - Waterson, David

AU - Fairlamb, Alan H.

AU - Wyatt, Paul G.

AU - Gilbert, Ian H.

AU - Frearson, Julie A.

N1 - This project was funded primarily by Medicines for Malaria Venture. We also like to acknowledge The Wellcome Trust for funding (Grant No.083481).

PY - 2017/11/7

Y1 - 2017/11/7

N2 - Background: Protein kinases have been shown to be key drug targets, especially in the area of oncology. It is of interested to explore the possibilities of protein kinases as a potential target class in Plasmodium spp., the causative agents of malaria. However, protein kinase biology in malaria is still being investigated. Therefore, rather than assaying against individual protein kinases, a library of 4,731 compounds with protein kinase inhibitor-like scaffolds was screened against the causative parasite, Plasmodium falciparum. This approach is more holistic and considers the whole kinome, making it possible to identify compounds that inhibit more than one P. falciparum protein kinase, or indeed other malaria targets.Results: As a result of this screen, 9 active compound series were identified; further validation was carried out on 4 of these series, with 3 being progressed into hits to lead chemistry. The detailed evaluation of one of these series is described.Discussion: This screening approach proved to be an effective way to identify series for further optimisation against malaria. Compound optimisation was carried out in the absence of knowledge of the molecular target. Some of the series had to be halted for various reasons. Mode of action studies to find the molecular target may be useful when problems prevent further chemical optimisation.Conclusions: Progressible series were identified through phenotypic screening of a relatively small focused kinase scaffold chemical library.

AB - Background: Protein kinases have been shown to be key drug targets, especially in the area of oncology. It is of interested to explore the possibilities of protein kinases as a potential target class in Plasmodium spp., the causative agents of malaria. However, protein kinase biology in malaria is still being investigated. Therefore, rather than assaying against individual protein kinases, a library of 4,731 compounds with protein kinase inhibitor-like scaffolds was screened against the causative parasite, Plasmodium falciparum. This approach is more holistic and considers the whole kinome, making it possible to identify compounds that inhibit more than one P. falciparum protein kinase, or indeed other malaria targets.Results: As a result of this screen, 9 active compound series were identified; further validation was carried out on 4 of these series, with 3 being progressed into hits to lead chemistry. The detailed evaluation of one of these series is described.Discussion: This screening approach proved to be an effective way to identify series for further optimisation against malaria. Compound optimisation was carried out in the absence of knowledge of the molecular target. Some of the series had to be halted for various reasons. Mode of action studies to find the molecular target may be useful when problems prevent further chemical optimisation.Conclusions: Progressible series were identified through phenotypic screening of a relatively small focused kinase scaffold chemical library.

U2 - 10.1186/s12936-017-2085-4

DO - 10.1186/s12936-017-2085-4

M3 - Article

VL - 16

SP - 1

EP - 11

JO - Malaria Journal

JF - Malaria Journal

SN - 1475-2875

M1 - 446

ER -