Biochemical Screening of Five Protein Kinases from Plasmodium falciparum against 14,000 Cell-Active Compounds.
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 developmen...
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2016-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC4774911?pdf=render |
| _version_ | 1818945511093174272 |
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| author | Gregory J Crowther Heidi K Hillesland Katelyn R Keyloun Molly C Reid Maria Jose Lafuente-Monasterio Sonja Ghidelli-Disse Stephen E Leonard Panqing He Jackson C Jones Mallory M Krahn Jack S Mo Kartheek S Dasari Anna M W Fox Markus Boesche Majida El Bakkouri Kasey L Rivas Didier Leroy Raymond Hui Gerard Drewes Dustin J Maly Wesley C Van Voorhis Kayode K Ojo |
| author_facet | Gregory J Crowther Heidi K Hillesland Katelyn R Keyloun Molly C Reid Maria Jose Lafuente-Monasterio Sonja Ghidelli-Disse Stephen E Leonard Panqing He Jackson C Jones Mallory M Krahn Jack S Mo Kartheek S Dasari Anna M W Fox Markus Boesche Majida El Bakkouri Kasey L Rivas Didier Leroy Raymond Hui Gerard Drewes Dustin J Maly Wesley C Van Voorhis Kayode K Ojo |
| author_sort | Gregory J Crowther |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-20T08:00:16Z |
| format | Article |
| id | doaj.art-5e2950d857f248d1802b59df2efcbcbc |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-20T08:00:16Z |
| publishDate | 2016-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-5e2950d857f248d1802b59df2efcbcbc2022-12-21T19:47:33ZengPublic Library of Science (PLoS)PLoS ONE1932-62032016-01-01113e014999610.1371/journal.pone.0149996Biochemical Screening of Five Protein Kinases from Plasmodium falciparum against 14,000 Cell-Active Compounds.Gregory J CrowtherHeidi K HilleslandKatelyn R KeylounMolly C ReidMaria Jose Lafuente-MonasterioSonja Ghidelli-DisseStephen E LeonardPanqing HeJackson C JonesMallory M KrahnJack S MoKartheek S DasariAnna M W FoxMarkus BoescheMajida El BakkouriKasey L RivasDidier LeroyRaymond HuiGerard DrewesDustin J MalyWesley C Van VoorhisKayode K OjoIn 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.http://europepmc.org/articles/PMC4774911?pdf=render |
| spellingShingle | Gregory J Crowther Heidi K Hillesland Katelyn R Keyloun Molly C Reid Maria Jose Lafuente-Monasterio Sonja Ghidelli-Disse Stephen E Leonard Panqing He Jackson C Jones Mallory M Krahn Jack S Mo Kartheek S Dasari Anna M W Fox Markus Boesche Majida El Bakkouri Kasey L Rivas Didier Leroy Raymond Hui Gerard Drewes Dustin J Maly Wesley C Van Voorhis Kayode K Ojo Biochemical Screening of Five Protein Kinases from Plasmodium falciparum against 14,000 Cell-Active Compounds. PLoS ONE |
| title | Biochemical Screening of Five Protein Kinases from Plasmodium falciparum against 14,000 Cell-Active Compounds. |
| title_full | Biochemical Screening of Five Protein Kinases from Plasmodium falciparum against 14,000 Cell-Active Compounds. |
| title_fullStr | Biochemical Screening of Five Protein Kinases from Plasmodium falciparum against 14,000 Cell-Active Compounds. |
| title_full_unstemmed | Biochemical Screening of Five Protein Kinases from Plasmodium falciparum against 14,000 Cell-Active Compounds. |
| title_short | Biochemical Screening of Five Protein Kinases from Plasmodium falciparum against 14,000 Cell-Active Compounds. |
| title_sort | biochemical screening of five protein kinases from plasmodium falciparum against 14 000 cell active compounds |
| url | http://europepmc.org/articles/PMC4774911?pdf=render |
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