Biochemical Screening of Five Protein Kinases from Plasmodium falciparum against 14,000 Cell-Active Compounds.

Autor:	Crowther GJ; Division of Allergy & Infectious Diseases, Department of Medicine, University of Washington, Seattle, Washington, United States of America., Hillesland HK; Division of Allergy & Infectious Diseases, Department of Medicine, University of Washington, Seattle, Washington, United States of America., Keyloun KR; Division of Allergy & Infectious Diseases, Department of Medicine, University of Washington, Seattle, Washington, United States of America., Reid MC; Division of Allergy & Infectious Diseases, Department of Medicine, University of Washington, Seattle, Washington, United States of America., Lafuente-Monasterio MJ; Tres Cantos Medicines Development Campus, GlaxoSmithKline, Tres Cantos, Madrid, Spain., Ghidelli-Disse S; Cellzome GmbH, Molecular Discovery Research, GlaxoSmithKline R&D, Heidelberg, Germany., Leonard SE; Department of Chemistry, University of Washington, Seattle, Washington, United States of America., He P; Division of Allergy & Infectious Diseases, Department of Medicine, University of Washington, Seattle, Washington, United States of America., Jones JC; Division of Allergy & Infectious Diseases, Department of Medicine, University of Washington, Seattle, Washington, United States of America., Krahn MM; Division of Allergy & Infectious Diseases, Department of Medicine, University of Washington, Seattle, Washington, United States of America., Mo JS; Division of Allergy & Infectious Diseases, Department of Medicine, University of Washington, Seattle, Washington, United States of America., Dasari KS; Division of Allergy & Infectious Diseases, Department of Medicine, University of Washington, Seattle, Washington, United States of America., Fox AM; Division of Allergy & Infectious Diseases, Department of Medicine, University of Washington, Seattle, Washington, United States of America., Boesche M; Cellzome GmbH, Molecular Discovery Research, GlaxoSmithKline R&D, Heidelberg, Germany., El Bakkouri M; Structural Genomics Consortium, University of Toronto, Toronto, Ontario, Canada., Rivas KL; Division of Allergy & Infectious Diseases, Department of Medicine, University of Washington, Seattle, Washington, United States of America., Leroy D; Drug Discovery, Medicines for Malaria Venture, Geneva, Switzerland., Hui R; Structural Genomics Consortium, University of Toronto, Toronto, Ontario, Canada., Drewes G; Cellzome GmbH, Molecular Discovery Research, GlaxoSmithKline R&D, Heidelberg, Germany., Maly DJ; Department of Chemistry, University of Washington, Seattle, Washington, United States of America., Van Voorhis WC; Division of Allergy & Infectious Diseases, Department of Medicine, University of Washington, Seattle, Washington, United States of America., Ojo KK; Division of Allergy & Infectious Diseases, Department of Medicine, University of Washington, Seattle, Washington, United States of America.
Jazyk:	angličtina
Zdroj:	PloS one [PLoS One] 2016 Mar 02; Vol. 11 (3), pp. e0149996. Date of Electronic Publication: 2016 Mar 02 (Print Publication: 2016).
DOI:	10.1371/journal.pone.0149996
Abstrakt:	In 2010 the identities of thousands of anti-Plasmodium compounds were released publicly to facilitate malaria drug development. Understanding these compounds' mechanisms of action--i.e., the specific molecular targets by which they kill the parasite--would further facilitate the drug development process. Given that kinases are promising anti-malaria targets, we screened ~14,000 cell-active compounds for activity against five different protein kinases. Collections of cell-active compounds from GlaxoSmithKline (the ~13,000-compound Tres Cantos Antimalarial Set, or TCAMS), St. Jude Children's Research Hospital (260 compounds), and the Medicines for Malaria Venture (the 400-compound Malaria Box) were screened in biochemical assays of Plasmodium falciparum calcium-dependent protein kinases 1 and 4 (CDPK1 and CDPK4), mitogen-associated protein kinase 2 (MAPK2/MAP2), protein kinase 6 (PK6), and protein kinase 7 (PK7). Novel potent inhibitors (IC50 < 1 μM) were discovered for three of the kinases: CDPK1, CDPK4, and PK6. The PK6 inhibitors are the most potent yet discovered for this enzyme and deserve further scrutiny. Additionally, kinome-wide competition assays revealed a compound that inhibits CDPK4 with few effects on ~150 human kinases, and several related compounds that inhibit CDPK1 and CDPK4 yet have limited cytotoxicity to human (HepG2) cells. Our data suggest that inhibiting multiple Plasmodium kinase targets without harming human cells is challenging but feasible.
Databáze:	MEDLINE
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