The spleen tyrosine kinase (SYK): A crucial therapeutic target for diverse liver diseases

Zhao, Yaping; Liu, Rongrong; Li, Miaomiao; Liu, Pengfei

doi:10.1016/j.heliyon.2022.e12130

Cited by 5 publications

(3 citation statements)

References 69 publications

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“…Attempts to identify the target of OGHL250 through the selection of parasite resistance to the compound were unsuccessful. OGHL250 is a known inhibitor of human spleen tyrosine kinase (Syk) for which inhibitory compounds have been developed to treat several diseases . Given OGHL250’s modest potency against parasite growth and poor inhibition of protein export, the compound could have multiple targets in P.…”

Section: Discussionmentioning

confidence: 99%

“…OGHL250 is a known inhibitor of human spleen tyrosine kinase (Syk) for which inhibitory compounds have been developed to treat several diseases. 46 Given OGHL250’s modest potency against parasite growth and poor inhibition of protein export, the compound could have multiple targets in P. falciparum including one or more of the parasite’s many kinases. 47 Activity against multiple parasite proteins would decrease the chances of recovering multiple resistance mutations in a single parasite, which may have been why resistance to OGHL250 was not recovered.…”

Section: Discussionmentioning

confidence: 99%

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A Pyridyl-Furan Series Developed from the Open Global Health Library Block Red Blood Cell Invasion and Protein Trafficking in Plasmodium falciparum through Potential Inhibition of the Parasite’s PI4KIIIB Enzyme

Ling,

Nguyen,

Looker

et al. 2023

ACS Infect. Dis.

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With the resistance increasing to current antimalarial medicines, there is an urgent need to discover new drug targets and to develop new medicines against these targets. We therefore screened the Open Global Health Library of Merck KGaA, Darmstadt, Germany, of 250 compounds against the asexual blood stage of the deadliest malarial parasite Plasmodium falciparum, from which eight inhibitors with low micromolar potency were found. Due to its combined potencies against parasite growth and inhibition of red blood cell invasion, the pyridyl-furan compound OGHL250 was prioritized for further optimization. The potency of the series lead compound (WEHI-518) was improved 250-fold to low nanomolar levels against parasite blood-stage growth. Parasites selected for resistance to a related compound, MMV396797, were also resistant to WEHI-518 as well as KDU731, an inhibitor of the phosphatidylinositol kinase PfPI4KIIIB, suggesting that this kinase is the target of the pyridyl-furan series. Inhibition of PfPI4KIIIB blocks multiple stages of the parasite's life cycle and other potent inhibitors are currently under preclinical development. MMV396797-resistant parasites possess an E1316D mutation in PfPKI4IIIB that clusters with known resistance mutations of other inhibitors of the kinase. Building upon earlier studies that showed that PfPI4KIIIB inhibitors block the development of the invasive merozoite parasite stage, we show that members of the pyridyl-furan series also block invasion and/or the conversion of merozoites into ring-stage intracellular parasites through inhibition of protein secretion and export into red blood cells.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

A Pyridyl-Furan Series Developed from the Open Global Health Library Block Red Blood Cell Invasion and Protein Trafficking in Plasmodium falciparum through Potential Inhibition of the Parasite’s PI4KIIIB Enzyme

Ling,

Nguyen,

Looker

et al. 2023

ACS Infect. Dis.

View full text Add to dashboard Cite

show abstract

“…Attempts to identify the target of OGHL250 through selection of parasite resistance to the compound were unsuccessful. OGHL250 is a known inhibitor of human spleen tyrosine kinase (Syk) for which inhibitory compounds have been developed to treat several diseases 44 . Given OGHL250's modest potency against parasite growth and poor inhibition of protein export, the compound could have multiple targets in P. falciparum including one or more of the parasite's many kinases 45 .…”

Section: Discussionmentioning

confidence: 99%

A pyridyl-furan series developed from Open Global Health Library blocks red blood cell invasion and protein trafficking inPlasmodium falciparumthrough potential inhibition of the parasite’s PI4KIIIb enzyme

Ling

Nguyen

Looker

et al. 2023

Preprint

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With resistance increasing to current antimalarial medicines, there is an urgent need to discover new drug targets and to develop new medicines against these targets. We therefore screened the Open Global Health Library of Merck KGaA, Darmstadt, Germany of 250 compounds against the asexual blood stage of the deadliest malarial parasite Plasmodium falciparum, from which eight inhibitors with low micromolar potency were found. Due to its combined potencies against parasite growth and inhibition of red blood cell invasion, the pyridyl-furan compound OGHL250, was prioritised for further optimisation. The potency of the series lead compound (WEHI-518) was improved 250-fold to low nanomolar levels against parasite blood-stage growth. Parasites selected for resistance to a related compound MMV396797, were also resistant to WEHI-518 as well as KDU731, an inhibitor of the phosphatidylinositol kinase PfPI4KIIIB, suggesting this kinase is the target of the pyridyl-furan series. Inhibition of PfPI4KIIIB blocks multiple stages of the parasites life cycle and other potent inhibitors are currently under preclinical development. MMV396797-resistant parasites possess an E1316D mutation in PfPKI4IIIB which clusters with known resistance mutations of other inhibitors of the kinase. Building upon earlier studies which showed that PfPI4KIIIB inhibitors block the development of the invasive merozoite parasite stage, we show that members of the pyridyl-furan series also block invasion and/or the conversion of merozoites into ring-stage intracellular parasites through inhibition of protein secretion and export into red blood cells.

show abstract

Microglia-induced neuroinflammation in hippocampal neurogenesis following traumatic brain injury

Navabi,

Badreh,

Khombi Shooshtari

et al. 2024

Heliyon

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The spleen tyrosine kinase (SYK): A crucial therapeutic target for diverse liver diseases

Cited by 5 publications

References 69 publications

A Pyridyl-Furan Series Developed from the Open Global Health Library Block Red Blood Cell Invasion and Protein Trafficking in Plasmodium falciparum through Potential Inhibition of the Parasite’s PI4KIIIB Enzyme

A Pyridyl-Furan Series Developed from the Open Global Health Library Block Red Blood Cell Invasion and Protein Trafficking in Plasmodium falciparum through Potential Inhibition of the Parasite’s PI4KIIIB Enzyme

A pyridyl-furan series developed from Open Global Health Library blocks red blood cell invasion and protein trafficking inPlasmodium falciparumthrough potential inhibition of the parasite’s PI4KIIIb enzyme

Microglia-induced neuroinflammation in hippocampal neurogenesis following traumatic brain injury

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