The Susceptibility of Trypanosomatid Pathogens to PI3/mTOR Kinase Inhibitors Affords a New Opportunity for Drug Repurposing

Abstract

BackgroundTarget repurposing utilizes knowledge of “druggable” targets obtained in one organism and exploits this information to pursue new potential drug targets in other organisms. Here we describe such studies to evaluate whether inhibitors targeting the kinase domain of the mammalian Target of Rapamycin (mTOR) and human phosphoinositide-3-kinases (PI3Ks) show promise against the kinetoplastid parasites Trypanosoma brucei, T. cruzi, Leishmania major, and L. donovani. The genomes of trypanosomatids encode at least 12 proteins belonging to the PI3K protein superfamily, some of which are unique to parasites. Moreover, the shared PI3Ks differ greatly in sequence from those of the human host, thereby providing opportunities for selective inhibition.Methodology/Principal FindingsWe focused on 8 inhibitors targeting mTOR and/or PI3Ks selected from various stages of pre-clinical and clinical development, and tested them against in vitro parasite cultures and in vivo models of infection. Several inhibitors showed micromolar or better efficacy against these organisms in culture. One compound, NVP-BEZ235, displayed sub-nanomolar potency, efficacy against cultured parasites, and an ability to clear parasitemia in an animal model of T. brucei rhodesiense infection.Conclusions/SignificanceThese studies strongly suggest that mammalian PI3/TOR kinase inhibitors are a productive starting point for anti-trypanosomal drug discovery. Our data suggest that NVP-BEZ235, an advanced clinical candidate against solid tumors, merits further investigation as an agent for treating African sleeping sickness.

Activation of AR Sensitizes Breast Carcinomas to NVP-BEZ235's Therapeutic Effect Mediated by PTEN and KLLN Upregulation

“…S7A). Multiple studies have reported that high doses of NVP-BEZ235 resulted in weight loss in mouse models (31,32). After 4 weeks of treatment, NVP-BEZ235 reduced mouse body weight in a dose-dependent manner (Supplementary Fig.…”

Identification and Characterization of Hundreds of Potent and Selective Inhibitors of Trypanosoma brucei Growth from a Kinase-Targeted Library Screening Campaign

“…During assay development, final experimental conditions were assessed in terms of DMSO and compound concentration, inoculum density and resazurin-dependent fluorescence, and validated with standard trypanocidal drugs and kinase inhibitors 14,28]. The selected compounds from the GSK collection were tested at 4 mM concentration in a single point assay to test their growth inhibition in a log-phase culture of T. b. brucei using the optimized assay conditions.…”

“…These target families include phosphodiesterases 11], histone deacetylases 12], and kinases 13,14,15,16,17].…”

Activity of 6-aryl-pyrrolo[2,3-d]pyrimidine-4-amines to Tetrahymena

“…The protozoacidal activity of the analogues was found to be highly 25 dependent on a 4-hydroxyl group at the 6-aryl ring, and a chiral 1-phenylethanamine substituent in posi- 26 tion 4. Further, the potency was affected by the aromatic substitution pattern of the phenylethanamine: 27 the unsubstituted, the meta-fluoro and the para-bromo substituted derivatives had the lowest minimum 28 protozoacidal concentrations (8)(9)(10)(11)(12)(13)(14)(15)(16) lg/mL). Surprisingly, both enantiomers were found to have high 29 potency suggesting that this compound class could have several modes of action.…”