2. Academic Validation
  3. DNDI-6174 is a preclinical candidate for visceral leishmaniasis that targets the cytochrome bc1

DNDI-6174 is a preclinical candidate for visceral leishmaniasis that targets the cytochrome bc1

  • Sci Transl Med. 2023 Dec 13;15(726):eadh9902. doi: 10.1126/scitranslmed.adh9902.
Stéphanie Braillard 1,  Martine Keenan 2,  Karen J Breese 2,  Jacob Heppell 2,  Michael Abbott 2,  Rafiqul Islam 2,  David M Shackleford 3,  Kasiram Katneni 3,  Elly Crighton 3,  Gong Chen 3,  Rahul Patil 3,  Given Lee 3,  Karen L White 3,  Sandra Carvalho 4,  Richard J Wall 4,  Giulia Chemi 5,  Fabio Zuccotto 5,  Silvia González 6,  Maria Marco 6,  Julianna Deakyne 7,  David Standing 8,  Gino Brunori 9,  Jonathan J Lyon 9,  Pablo Castañeda-Casado 10,  Isabel Camino 10,  Maria S Martinez Martinez 10,  Bilal Zulfiqar 11,  Vicky M Avery 11,  Pim-Bart Feijens 12,  Natascha Van Pelt 12,  An Matheeussen 12,  Sarah Hendrickx 12,  Louis Maes 12,  Guy Caljon 12,  Vanessa Yardley 13,  Susan Wyllie 4,  Susan A Charman 3,  Eric Chatelain 1
Affiliations

Affiliations

  • 1 Drugs for Neglected Diseases initiative (DNDi), Chemin Camille-Vidart 15, 1202 Geneva, Switzerland.
  • 2 Epichem Pty Ltd., Perth, Western Australia, Australia.
  • 3 Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville 3052, Australia.
  • 4 Wellcome Centre for Anti-infectives Research, School of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, UK.
  • 5 Drug Discovery Unit, Wellcome Centre for Anti-infectives Research, School of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, UK.
  • 6 Global Health Medicines R&D, GlaxoSmithKline, Tres Cantos, Madrid 28760, Spain.
  • 7 Global Investigative Safety, GSK, Collegeville, PA, USA.
  • 8 Medicine Design, GSK, Stevenage, UK.
  • 9 Global Investigative Safety, GSK, Ware, UK.
  • 10 Discovery DMPK, GSK, Tres Cantos, Madrid, Spain.
  • 11 Discovery Biology, Griffith University, Nathan, Queensland 4111, Australia.
  • 12 Laboratory of Microbiology, Parasitology and Hygiene (LMPH), University of Antwerp, Universiteitsplein 1, 2610 Wilrijk, Belgium.
  • 13 Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, UK.
PMID: 38091406 DOI: 10.1126/scitranslmed.adh9902
Abstract

New drugs for visceral leishmaniasis that are safe, low cost, and adapted to the field are urgently required. Despite concerted efforts over the last several years, the number of new chemical entities that are suitable for clinical development for the treatment of Leishmania remains low. Here, we describe the discovery and preclinical development of DNDI-6174, an inhibitor of Leishmania cytochrome bc1 complex activity that originated from a phenotypically identified pyrrolopyrimidine series. This compound fulfills all target candidate profile criteria required for progression into preclinical development. In addition to good metabolic stability and pharmacokinetic properties, DNDI-6174 demonstrates potent in vitro activity against a variety of Leishmania species and can reduce Parasite burden in animal models of Infection, with the potential to approach sterile cure. No major flags were identified in preliminary safety studies, including an exploratory 14-day toxicology study in the rat. DNDI-6174 is a cytochrome bc1 complex inhibitor with acceptable development properties to enter preclinical development for visceral leishmaniasis.

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