DNDI-6148: A Novel Benzoxaborole Preclinical Candidate for the Treatment of Visceral Leishmaniasis
- Charles E. Mowbray*1, Stéphanie Braillard1, Paul A. Glossop2, Gavin A. Whitlock2, Robert T. Jacobs3, Jason Speake3, Bharathi Pandi3, Bakela Nare3, Louis Maes4, Vanessa Yardley5, Yvonne Freund6, Richard J. Wall7, Sandra Carvalho7, Davide Bello7, Magali Van den Kerkhof4, Guy Caljon4, Ian H. Gilbert7, Victoriano Corpas-Lopez7, Iva Lukac7, Stephen Patterson7, Fabio Zuccotto7, Susan Wyllie*7
- 1Drugs for Neglected Diseases initiative (DNDi), 15 Chemin Louis-Dunant, 1202 Geneva, Switzerland
- 2Sandexis Medicinal Chemistry Ltd, Innovation House, Discovery Park, Ramsgate Road, Sandwich, Kent CT13 9ND, U.K.
- 3Scynexis, 3501 C Tricenter Boulevard, Durham, North Carolina 27713, United States
- 4Laboratory for Microbiology, Parasitology and Hygiene (LMPH), University of Antwerp, Universiteitsplein 1, 2610 Wilrijk, Antwerp, Belgium
- 5Faculty of Infectious and Tropical Diseases, London School of Hygiene & Tropical Medicine, Keppel Street, London WC1E 7HT, U.K.
- 6Anacor Pharmaceuticals, 1020 East Meadow Circle, Palo Alto, California 94303, United States
- 7Division of Biological Chemistry and Drug Discovery, Wellcome Centre for Anti-infectives Research, School of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, U.K.Read the publication that featured this abstract
Visceral leishmaniasis (VL) is a parasitic disease endemic across multiple regions of the world and is fatal if untreated. Current therapies are unsuitable, and there is an urgent need for safe, short-course, and low-cost oral treatments to combat this neglected disease. The benzoxaborole chemotype has previously delivered clinical candidates for the treatment of other parasitic diseases. Here, we describe the development and optimization of this series, leading to the identification of compounds with potent in vitro and in vivo antileishmanial activity. The lead compound (DNDI-6148) combines impressive in vivo efficacy (>98% reduction in parasite burden) with pharmaceutical properties suitable for onward development and an acceptable safety profile. Detailed mode of action studies confirm that DNDI-6148 acts principally through the inhibition of Leishmania cleavage and polyadenylation specificity factor (CPSF3) endonuclease. As a result of these studies and its promising profile, DNDI-6148 has been declared a preclinical candidate for the treatment of VL.
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