846. Beyond imatinib: Repurposed FDA-approved protein kinase inhibitors as macrofilaricides
Session: Oral Abstract Session: Global Diseases at Home and Abroad
Thursday, October 27, 2016: 2:30 PM
Room: 288-290
Background: Despite ivermectin-based annual mass drug administration (MDA) for the elimination of onchocerciasis (‘river blindness’), there are many regions in Africa where transmission of Onchocerca volvulus (Ov) has not been interrupted, including areas where MDA has been used for over 20 years. The current ivermectin-based strategy kills the microfilariae (mf) but has little to no effect on the adult stage. With the completion of Ov genome, several protein kinases encoded by all filarial genomes were found to have human homologues with FDA-approved inhibitors. We have previously shown that in vitro imatinib is microfilaricidal at pharmacologically achievable concentrations and may have sterilizing effects in adults.

Methods: An in vitro screen of Brugia malayi with 8 other protein kinase inhibitors identified 3 with macrofilaricidal activity. These drugs, sorafenib (b-Raf inhibitor), lapatinib (EGFR inhibitor), and temsirolimus (mTOR inhibitor) were then tested in vitro against adult male O. gutterosa, a cattle parasite. The latter 2 drugs were found to affect worm viability. Thus, lapatinib and temsirolimus were tested in vitro against Ov. Using varying concentrations of the 2 drugs in a 6-day L3 to L4 molting assay it was determined that temsirolimus and lapatinib were both able to prevent molting (IC50 of 3.7μM and 8.3μM, respectively). Both compounds were also tested in vitro against early Ov adults (L5) using a novel in vitro culturing system. L5s (Day 75) were exposed to 30μM and 10μM of each drug for 15 days. Mobility and viability were assessed periodically until day 29.

Results: Lapatinib at 30μM only achieved 50% inhibition of motility and 50% of killing at day 29. However, temsirolimus was highly active, and at 30μM caused 100% inhibition of motility by day 17, and at 10μM 100% inhibition of motility and viability by day 29. Electron microscopy confirmed extensive damage in the killed L5s. Proteomic data and 3-dimensional protein modeling revealed that stage-specific protein expression and computed degree of homology between the Ov and human proteins were predictive of in vitro drug efficacies against Ov.

Conclusion: Given these results, temsirolimus should be investigated further to assess its in vivo efficacy as a macrofilaricide using doses approved and tolerable for humans.

Elise O'connell, MD1, Nancy Tricoche, MS2, Aaron Bell, PhD2, Gargi Pal, PhD2, Sasisekhar Bennuru, PhD1, Sara Lustigman, PhD2 and Thomas Nutman, MD, FIDSA1, (1)Laboratory of Parasitic Diseases, National Institutes of Health, National Institute of Allergy and Infectious Diseases, Bethesda, MD, (2)New York Blood Center, New York, NY


E. O'connell, None

N. Tricoche, None

A. Bell, None

G. Pal, None

S. Bennuru, None

S. Lustigman, None

T. Nutman, None

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