Ponatinib, Lestaurtinib, and mTOR/PI3K Inhibitors Are Promising Repurposing Candidates against Entamoeba histolytica.

Abstract

Dysentery caused by Entamoeba histolytica affects millions of people annually. Current treatment regimens are based on metronidazole to treat invasive parasites combined with paromomycin for luminal parasites. Issues with treatment include significant side effects, inability to easily treat breastfeeding and pregnant women, the use of two sequential agents, and concern that all therapy is based on nitroimidazole agents, with no alternatives if clinical resistance emerges. Thus, the need for new drugs against amebiasis is urgent. To identify new therapeutic candidates, we screened 11,948 compounds assembled for the ReFRAME (Repurposing, Focused Rescue, and Accelerated Medchem) library against E. histolytica trophozoites. We identified 159 hits in the primary screen at 10 μM, and 46 compounds were confirmed in secondary assays. Overall, 26 were selected as priority molecules for further investigation, including 6 FDA approved, 5 orphan designations, and 15 that are currently in clinical trials (3 phase III, 7 phase II, and 5 phase I). We found that all 26 compounds are active against metronidazole-resistant E. histolytica, and 24 are able to block parasite recrudescence after drug removal. Additionally, 14 are able to inhibit encystation and 2 (lestaurtinib and LY-2874455) are active against mature cysts. Two classes of compounds are most interesting for further investigations: (i) the Bcr-Abl tyrosine kinase (TK) inhibitors, with ponatinib (50% effective concentration [EC50], 0.39) as the most potent; and (ii) mTOR or phosphatidylinositol 3-kinase (PI3K) inhibitors, with 8 compounds in clinical development, of which 4 have nanomolar potency. Overall, these are promising candidates and represent a significant advance for development of drugs against E. histolytica.