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

• Published in: Science translational medicine 2023-12, Vol.15 (726), p.eadh9902-eadh9902
• Main Authors: Braillard, Stéphanie, Keenan, Martine, Breese, Karen J., Heppell, Jacob, Abbott, Michael, Islam, Rafiqul, Shackleford, David M., Katneni, Kasiram, Crighton, Elly, Chen, Gong, Patil, Rahul, Lee, Given, White, Karen L., Carvalho, Sandra, Wall, Richard J., Chemi, Giulia, Zuccotto, Fabio, González, Silvia, Marco, Maria, Deakyne, Julianna, Standing, David, Brunori, Gino, Lyon, Jonathan J., Castañeda Casado, Pablo, Camino, Isabel, Martinez, Maria S. Martinez, Zulfiqar, Bilal, Avery, Vicky M., Feijens, Pim-Bart, Van Pelt, Natascha, Matheeussen, An, Hendrickx, Sarah, Maes, Louis, Caljon, Guy, Yardley, Vanessa, Wyllie, Susan, Charman, Susan A., Chatelain, Eric
• Format: Article
• Language: English
• ISSN: 1946-6234; 1946-6242
• DOI: 10.1126/scitranslmed.adh9902

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 with novel mechanisms of action that are suitable for clinical development remains low. Here, we describe the development of DNDI-6174, an inhibitor of Leishmania cytochrome b 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 potential for sterile cure. No significant flags were identified in preliminary safety studies, including an exploratory 14-day toxicology study in the rat. DNDI-6174 represents the first cytochrome b inhibitor to enter preclinical development for visceral leishmaniasis.