Drug Repurposing of Quisinostat to Discover Novel Plasmodium falciparum HDAC1 Inhibitors with Enhanced Triple-Stage Antimalarial Activity and Improved Safety

Abstract

Our previous work found that the clinical histone deacetylase (HDAC) inhibitor quisinostat exhibited a significant antimalarial effect but with severe toxicity. In this work, 35 novel derivatives were designed and synthesized based on quisinostat as the lead compound, and their in vitro antimalarial activities and cytotoxicities were systematically evaluated. Among them, JX35 showed potent inhibition against both wild-type and multidrug-resistant parasite strains and displayed a significant in vivo killing effect against all life cycles of parasites, including the blood stage, liver stage, and gametocyte stage, indicating its potential for the simultaneous treatment, chemoprevention, and blockage of malaria transmission. Compared with quisinostat, JX35 exhibited stronger antimalarial efficacy, more adequate safety, and good pharmacokinetic properties. Additionally, mechanistic studies via molecular docking studies, induced PfHDAC1/2 knockdown assays, and PfHDAC1 enzyme inhibition assays jointly indicated that the antimalarial target of JX35 was PfHDAC1. In summary, we discovered the promising candidate PfHDAC1 inhibitor JX35, which showed stronger triple-stage antimalarial effects and lower toxicity than quisinostat.

Advances in malaria pharmacology and the online guide to MALARIA PHARMACOLOGY: IUPHAR review 38

“…Recently, an inhibitor screen on 350 diverse epigenetic modifiers against different stages of P. falciparum parasites (Vanheer et al, 2020) identified active compounds, seven of which were HDAC inhibitors, with quisinostat being the most potent. Wang et al modified quisinostat by replacing the 4‐aminomethylpiperidine moiety with a 2,6‐diazaspiro[3.4]octane moiety (Wang et al, 2022). Out of 35 derivatives (JX1‐JX35), JX35 showed highest inhibitory activity against different stages (blood, liver and gametocyte) of P. falciparum with IC 50 values of <2 nM against both 3D7 and Dd2 strains.…”

Harnessing the cyclization strategy for new drug discovery

“…21 , Pf 3D7 IC 50 = 5.2 nmol/L, Pf Dd2 IC 50 = 7.1 nmol/L) and attenuated cytotoxicity against two human cell lines (HepG2 IC 50 = 264 nmol/L, 293T IC 50 = 241 nmol/L). Further optimization gave compound JX35, which showed a stronger triple-stage (the blood stage, liver stage, and gametocyte stage) antimalarial effect ( Pf 3D7 IC 50 = 1.26 nmol/L, Pf Dd2 IC 50 = 1.61 nmol/L), increased safety (HepG2 IC 50 = 1.02 μmol/L, 293T IC 50 = 1.21 μmol/L), and good pharmacokinetic properties 129 .

Figure 21 Discovery of the Pf HDAC1 inhibitor JX35.

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Discovery of Novel 1,2,3,4-Tetrahydrobenzofuro[2,3-c]pyridine Histone Deacetylase Inhibitors for Efficient Treatment of Hepatocellular Carcinoma

“…Histone deacetylases (HDACs) are an important component of epigenetic factors to catalyze the removal of acetyl and acyl groups from the modified ε-amino moiety of lysine in histone tails, thereby playing an essential role in the regulation of target gene expression. , The dysregulation of HDAC expression has been implicated in various cancer types, making HDACs attractive targets for cancer therapy. − Correspondingly, there were many endeavors that contributed to the development of HDAC inhibitors (HDACis) as a new therapeutic treatment, including pan-HDACis, − subtype-selective HDACiss, − and dual-target inhibitors based on HDAC. − Notably, five HDACis, namely, vorinostat (SAHA), belinostat, panobinostat, romidepsin, and chidamide, have been approved for the treatment of T-cell lymphoma and multiple myeloma (Figure ). Besides, several HDACis have been launched in clinical trials; for instance, abexinostat was in the phase III stage of a clinical trial for the treatment of renal carcinoma and lymphoma.…”