title: The susceptibility of trypanosomatid pathogens to PI3/mTOR kinase inhibitors affords a new opportunity for drug repurposing.
abstract: BACKGROUND
  Target 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.
  
  
  RESULTS
  We 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
  These 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.
authors: Instituto de Parasitología y Biomedicina "López-Neyra" Consejo Superior de Investigaciones Cientificas, Granada, Spain.
authors: Rosario
authors: R
authors: Diaz-Gonzalez
authors: F Matthew
authors: FM
authors: Kuhlmann
authors: Cristina
authors: C
authors: Galan-Rodriguez
authors: Luciana
authors: L
authors: Madeira da Silva
authors: Manuel
authors: M
authors: Saldivia
authors: Caitlin E
authors: CE
authors: Karver
authors: Ana
authors: A
authors: Rodriguez
authors: Stephen M
authors: SM
authors: Beverley
authors: Miguel
authors: M
authors: Navarro
authors: Michael P
authors: MP
authors: Pollastri
mesh_terms: D000818:Animals; D000981:Antiprotozoal Agents / Q000008:administration & dosage / Q000494:pharmacology*; D053492:Elafin / Q000037:antagonists & inhibitors; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D018320:Leishmania major / Q000187:drug effects; D016773:Leishmaniasis, Cutaneous / Q000188:drug therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D018512:Parasitemia / Q000188:drug therapy; D021261:Parasitic Sensitivity Tests; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D014345:Trypanosoma / Q000187:drug effects*; D014346:Trypanosoma brucei brucei / Q000187:drug effects; D014352:Trypanosomiasis / Q000188:drug therapy*
chemical_list: D000981:Antiprotozoal Agents; D053492:Elafin; C506806:PI3 protein, human; D047428:Protein Kinase Inhibitors; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases