Exploration of 3-methylisoquinoline-4-carbonitriles as protein kinase A inhibitors of Plasmodium falciparum

Buskes, Melissa J; Harvey, Katherine; Prinz, Boris; Crabb, Brendan S.; Gilson, Paul R.; Wilson, David J.; Abbott, Belinda M.

doi:10.1016/j.bmc.2016.03.048

Cited by 12 publications

(11 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We found that egress was not blocked by the compounds but invasion was, with a 50% inhibitory concentration (IC 50 ) value below 10 µM 24 . However, kinase activity assays with parasite-sourced PfPKA and exogenous cAMP indicated that none of our compounds inhibited PfPKA activity at low µM levels, unlike the commonly used PKA inhibitor H89 25 .…”

Section: Introductionmentioning

confidence: 73%

A 4-cyano-3-methylisoquinoline inhibitor of Plasmodium falciparum growth targets the sodium efflux pump PfATP4

Gilson

Kumarasingha

Thompson

et al. 2019

Sci Rep

Self Cite

View full text Add to dashboard Cite

We developed a novel series of antimalarial compounds based on a 4-cyano-3-methylisoquinoline. Our lead compound MB14 achieved modest inhibition of the growth in vitro of the human malaria parasite, Plasmodium falciparum . To identify its biological target we selected for parasites resistant to MB14. Genome sequencing revealed that all resistant parasites bore a single point S374R mutation in the sodium (Na + ) efflux transporter PfATP4. There are many compounds known to inhibit PfATP4 and some are under preclinical development. MB14 was shown to inhibit Na + dependent ATPase activity in parasite membranes, consistent with the compound targeting PfATP4 directly. PfATP4 inhibitors cause swelling and lysis of infected erythrocytes, attributed to the accumulation of Na + inside the intracellular parasites and the resultant parasite swelling. We show here that inhibitor-induced lysis of infected erythrocytes is dependent upon the parasite protein RhopH2, a component of the new permeability pathways that are induced by the parasite in the erythrocyte membrane. These pathways mediate the influx of Na + into the infected erythrocyte and their suppression via RhopH2 knockdown limits the accumulation of Na + within the parasite hence protecting the infected erythrocyte from lysis. This study reveals a role for the parasite-induced new permeability pathways in the mechanism of action of PfATP4 inhibitors.

show abstract

Section: Introductionmentioning

confidence: 73%

A 4-cyano-3-methylisoquinoline inhibitor of Plasmodium falciparum growth targets the sodium efflux pump PfATP4

Gilson

Kumarasingha

Thompson

et al. 2019

Sci Rep

Self Cite

View full text Add to dashboard Cite

show abstract

“…A homology model of the Pf PKA catalytic subunit was built based on the human crystal structure, and dynamic molecular modeling was used to identify strong binding ligands. 84 Synthesis of these ligands and testing against Pf 3D7 and multidrug-resistant Pf W2 strain showed mid-micromolar activities. In further studies, it was revealed that these compounds have no effect on Pf PKA.…”

Section: Agcmentioning

confidence: 99%

Plasmodial Kinase Inhibitors: License to Cure?

et al. 2018

View full text Add to dashboard Cite

Advances in the genetics, function, and stage-specificity of Plasmodium kinases has driven robust efforts to identify targets for the design of antimalarial therapies. Reverse genomics following phenotypic screening against Plasmodia or related parasites has uncovered vulnerable kinase targets including PI4K, PKG, and GSK-3, an approach bolstered by access to human disease-directed kinase libraries. Alternatively, screening compound libraries against Plasmodium kinases has successfully led to inhibitors with antiplasmodial activity. As with other therapeutic areas, optimizing compound ADMET and PK properties in parallel with target inhibitory potency and whole cell activity becomes paramount toward advancing compounds as clinical candidates. These and other considerations will be discussed in the context of progress achieved toward deriving important, novel mode-of-action kinase-inhibiting antimalarial medicines.

show abstract

“…Further evaluation of the physicochemical properties and in vitro activity of these compounds against the whole-cell parasite has not yet been reported. [83] attempted to develop Pf PKA inhibitors using the commercially available PKA inhibitor 3-methylisoquinoline-4-carbonitrile (33, Figure 14) as a starting point. They studied the interactions of compound 33 and a series of substituted isoquinolines (e.g., 34, Figure 14) with a Pf PKA homology model.…”

Section: Pf3d7 Blood Stage Ec50mentioning

confidence: 99%

An Update on Development of Small-Molecule Plasmodial Kinase Inhibitors

et al. 2020

View full text Add to dashboard Cite

Malaria control relies heavily on the small number of existing antimalarial drugs. However, recurring antimalarial drug resistance necessitates the continual generation of new antimalarial drugs with novel modes of action. In order to shift the focus from only controlling this disease towards elimination and eradication, next-generation antimalarial agents need to address the gaps in the malaria drug arsenal. This includes developing drugs for chemoprotection, treating severe malaria and blocking transmission. Plasmodial kinases are promising targets for next-generation antimalarial drug development as they mediate critical cellular processes and some are active across multiple stages of the parasite’s life cycle. This review gives an update on the progress made thus far with regards to plasmodial kinase small-molecule inhibitor development.

show abstract

Exploration of 3-methylisoquinoline-4-carbonitriles as protein kinase A inhibitors of Plasmodium falciparum

Cited by 12 publications

References 37 publications

A 4-cyano-3-methylisoquinoline inhibitor of Plasmodium falciparum growth targets the sodium efflux pump PfATP4

A 4-cyano-3-methylisoquinoline inhibitor of Plasmodium falciparum growth targets the sodium efflux pump PfATP4

Plasmodial Kinase Inhibitors: License to Cure?

An Update on Development of Small-Molecule Plasmodial Kinase Inhibitors

Contact Info

Product

Resources

About