Discovery of FNDR-20123, a histone deacetylase inhibitor for the treatment of Plasmodium falciparum malaria

Abstract

Background Emergence of anti-malarial drug resistance and perpetual increase in malaria incidence necessitates the development of novel anti-malarials. Histone deacetylases (HDAC) has been shown to be a promising target for malaria, despite this, there are no HDAC inhibitors in clinical trials for malaria treatment. This can be attributed to the poor pharmacokinetics, bioavailability and selectivity of the HDAC inhibitors. Methods A collection of HDAC inhibitors were screened for anti-malarial activity, and the best candidate was profiled in parasite-killing kinetics, growth inhibition of sensitive and multi-drug resistant (MDR) strains and against gametocytes. Absorption, distribution, metabolism and excretion pharmacokinetics (ADME-PK) parameters of FNDR-20123 were determined, and in vivo efficacy was studied in a mouse model for Plasmodium falciparum infection. Results A compound library of HDAC inhibitors (180 in number) was screened for anti-malarial activity, of which FNDR-20123 was the most potent candidate. The compound had been shown to inhibit Plasmodium HDAC with IC50 of 31 nM and human HDAC with IC50 of 3 nM. The IC50 obtained for P. falciparum in asexual blood-stage assay was 42 nM. When compared to atovaquone and pyrimethamine, the killing profiles of FNDR-20123 were better than atovaquone and comparable to pyrimethamine. The IC50 values for the growth inhibition of sensitive and MDR strains were similar, indicating that there is no cross-resistance and a low risk of resistance development. The selected compound was also active against gametocytes, indicating a potential for transmission control: IC50 values being 190 nM for male and > 5 µM for female gametocytes. FNDR-20123 is a stable candidate in human/mouse/rat liver microsomes (> 75% remaining post 2-h incubation), exhibits low plasma protein binding (57% in humans) with no human Ether-à-go–go-Related Gene (hERG) liability (> 100 µM), and does not inhibit any of the cytochrome P450 (CYP) isoforms tested (IC50 > 25 µM). It also shows negligible cytotoxicity to HepG-2 and THP-1 cell lines. The oral pharmacokinetics in rats at 100 mg/kg body weight shows good exposures (Cmax = 1.1 µM) and half-life (T1/2 = 5.5 h). Furthermore, a 14-day toxicokinetic study at 100 mg/kg daily dose did not show any abnormality in body weight or gross organ pathology. FNDR-20123 is also able to reduce parasitaemia significantly in a mouse model for P. falciparum infection when dosed orally and subcutaneously. Conclusion FNDR-20123 may be a suitable candidate for the treatment of malaria, which can be further developed.

Koshidacins A and B, Antiplasmodial Cyclic Tetrapeptides from the Okinawan Fungus Pochonia boninensis FKR-0564

“…Apicidin was also reported to exhibit a potent histone deacetylase (HDAC) inhibitor (IC 50 = 0.7 nM). There is structural diversity among HDAC inhibitors, including cyclic peptides such as apicidin and its analogs, hydroxamates such as suberoylanilide hydroxamic acid, trichostatin A, WR301801, and FNDR-20123, some of which were reported to display antimalarial activity by P. falciparum HDAC inhibition . Therefore, the mode of action of koshidacins in antiplasmodial activity might be HDAC inhibition.…”

Effects of Structurally Different HDAC Inhibitors against Trypanosoma cruzi, Leishmania, and Schistosoma mansoni

“… 17 − 19 As these features are also common to cancer cells, the use of epi-drugs developed for cancer diseases are considered as a new promising strategy for treating parasitic diseases, also because this piggyback approach can allow faster identification of new lead compounds. 1 , 20 , 21 …”

“…17−19 As these features are also common to cancer cells, the use of epi-drugs developed for cancer diseases are considered as a new promising strategy for treating parasitic diseases, also because this piggyback approach can allow faster identification of new lead compounds. 1,20,21 Histone deacetylases (HDACs) are known to silence critical regulatory pathways, including transcriptional regulation, 22 cell-cycle progression, 23 and pro-apoptotic programs. 24 Among the HDAC inhibitors (HDACi) approved for clinical use in cancer, vorinostat, romidepsin, belinostat, and panobinostat were tested in Leishmania at 10 and 20 μM and were ineffective and/or exhibited too high toxicity for macrophages.…”

“…Epigenetic mechanisms and changes in chromatin structure play an important role in parasitic development, and the impact of histone-modifying/interacting proteins is expected to be strong in parasites with complex life cycles and multiple developmental stages. Recent studies have shown the role played by these conserved proteins in the capacity of parasites to adapt to different environments quickly, evade host immune responses, or alter their phenotypes at several critical points of their life cycles. − As these features are also common to cancer cells, the use of epi-drugs developed for cancer diseases are considered as a new promising strategy for treating parasitic diseases, also because this piggyback approach can allow faster identification of new lead compounds. ,, …”

QSAR Classification Models for Prediction of Hydroxamate Histone Deacetylase Inhibitor Activity against Malaria Parasites

“…falciparum HDAC proteins (only Pf HDAC1 is available but has low purity), the absence of any Pf HDAC crystal structures, and the availability of a robust in silico homology model for only Pf HDAC1, − phenotypic assay screening has been the primary mechanism to identify HDAC inhibitors that can inhibit P. falciparum growth. ,,− However, as the screening of large compound sets can be expensive and time-consuming, an in silico quantitative structure–activity relationships (QSAR) model would be a useful tool to facilitate antiplasmodial HDAC inhibitor drug discovery efforts.…”