A novel multistage antiplasmodial inhibitor targeting Plasmodium falciparum histone deacetylase 1

Although artemisinin combination therapies have succeeded in reducing the global burden of malaria, multidrug resistance of the deadliest malaria parasite, Plasmodium falciparum, is emerging worldwide. Innovative antimalarial drugs that kill all life-cycle stages of malaria parasites are urgently needed. Here, we report the discovery of the compound JX21108 with broad antiplasmodial activity against multiple life-cycle stages of malaria parasites. JX21108 was developed from chemical optimization of quisinostat, a histone deacetylase inhibitor. We identified P. falciparum histone deacetylase 1 (PfHDAC1), an epigenetic regulator essential for parasite growth and invasion, as a molecular target of JX21108. PfHDAC1 knockdown leads to the downregulation of essential parasite genes, which is highly consistent with the transcriptomic changes induced by JX21108 treatment. Collectively, our data support that PfHDAC1 is a potential drug target for overcoming multidrug resistance and that JX21108 treats malaria and blocks parasite transmission simultaneously.

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S1096 Quisinostat (JNJ-26481585) 2HCl Quisinostat (JNJ-26481585) 2HCl is a novel second-generation HDAC inhibitor with highest potency for HDAC1 with IC50 of 0.11 nM in a cell-free assay, modest potent to HDACs 2, 4, 10, and 11; greater than 30-fold selectivity against HDACs 3, 5, 8, and 9 and lowest potency to HDACs 6 and 7. Phase 2.

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