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

Stéphanie Braillard; Martine Keenan; Karen J. Breese; Jacob Heppell; Michael Abbott; Rafiqul Islam; David M. Shackleford; Kasiram Katneni; Elly Crighton; Gong Chen; Rahul Patil; Given Lee; Karen L. White; Sandra Carvalho; Richard J. Wall; Giulia Chemi; Fabio Zuccotto; Silvia Gonzalez; Maria Marco; Julianna Deakyne; David Standing; Gino Brunori; Jonathan J. Lyon; Pablo Castañeda-Casado; Isabel Camino; Maria S. Martinez Martinez; Bilal Zulfiqar; Vicky M. Avery; Pim-Bart Feijens; Natascha Van Pelt; An Matheeussen; Sarah Hendrickx; Louis Maes; Guy Caljon; Vanessa Yardley; Susan Wyllie; Susan A. Charman; Eric Chatelain

doi:10.1126/scitranslmed.adh9902

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

Stéphanie Braillard, Martine Keenan, Karen J. Breese, Jacob Heppell, Michael Abbott, Rafiqul Islam, David M. Shackleford, Kasiram Katneni, Elly Crighton, Gong Chen, Rahul Patil, Given Lee, Karen L. White, Sandra Carvalho, Richard J. Wall, Giulia Chemi, Fabio Zuccotto, Silvia Gonzalez, Maria Marco, Julianna DeakyneDavid Standing, Gino Brunori, Jonathan J. Lyon, Pablo Castañeda-Casado, Isabel Camino, Maria S. Martinez Martinez, Bilal Zulfiqar, Vicky M. Avery, Pim-Bart Feijens, Natascha Van Pelt, An Matheeussen, Sarah Hendrickx, Louis Maes, Guy Caljon, Vanessa Yardley, Susan Wyllie (Lead / Corresponding author), Susan A. Charman (Lead / Corresponding author), Eric Chatelain (Lead / Corresponding author)

Biological Chemistry and Drug Discovery

Research output: Contribution to journal › Article › peer-review

10 Citations (Scopus)

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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.

Original language	English
Article number	eadh9902
Number of pages	15
Journal	Science Translational Medicine
Volume	15
Issue number	726
DOIs	https://doi.org/10.1126/scitranslmed.adh9902
Publication status	Published - 13 Dec 2023

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10.1126/scitranslmed.adh9902

Author Accepted ManuscriptAccepted author manuscript, 2.51 MBLicence: CC BY

1 Finished
2 Active

A Platform for Drug Target Deconvolution and Exploitation
Gilbert, I. (Investigator), Horn, D. (Investigator), Pawlowic, M. C. (Investigator), Wyatt, P. (Investigator) & Wyllie, S. (Investigator)
31/12/20 → 30/05/25
Project: Research
Wellcome Centre for Anti-Infectives Research
Cook, S. (Investigator), De Rycker, M. (Investigator), Fairlamb, A. (Investigator), Ferguson, M. (Investigator), Field, M. (Investigator), Gilbert, I. (Investigator), Gray, D. (Investigator), Horn, D. (Investigator), Pawlowic, M. C. (Investigator), Read, K. (Investigator), Wyatt, P. (Investigator) & Wyllie, S. (Investigator)
1/04/17 → 31/03/25
Project: Research
Chemical Biology: Leveraging Phenotypic Hits Against Kinetoplastids (Strategic Grant)
Fairlamb, A. (Investigator), Field, M. (Investigator), Gilbert, I. (Investigator), Gray, D. (Investigator), Horn, D. (Investigator) & Wyatt, P. (Investigator)
1/01/15 → 31/12/20
Project: Research

Cite this

Braillard, S., Keenan, M., Breese, K. J., Heppell, J., Abbott, M., Islam, R., Shackleford, D. M., Katneni, K., Crighton, E., Chen, G., Patil, R., Lee, G., White, K. L., Carvalho, S., Wall, R. J., Chemi, G., Zuccotto, F., Gonzalez, S., Marco, M., ... Chatelain, E. (2023). DNDI-6174 is a preclinical candidate for visceral leishmaniasis that targets the cytochrome bc1. Science Translational Medicine, 15(726), Article eadh9902. https://doi.org/10.1126/scitranslmed.adh9902

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title = "DNDI-6174 is a preclinical candidate for visceral leishmaniasis that targets the cytochrome bc1",

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.",

author = "St{\'e}phanie Braillard and Martine Keenan and Breese, {Karen J.} and Jacob Heppell and Michael Abbott and Rafiqul Islam and Shackleford, {David M.} and Kasiram Katneni and Elly Crighton and Gong Chen and Rahul Patil and Given Lee and White, {Karen L.} and Sandra Carvalho and Wall, {Richard J.} and Giulia Chemi and Fabio Zuccotto and Silvia Gonzalez and Maria Marco and Julianna Deakyne and David Standing and Gino Brunori and Lyon, {Jonathan J.} and Pablo Casta{\~n}eda-Casado and Isabel Camino and {Martinez Martinez}, {Maria S.} and Bilal Zulfiqar and Avery, {Vicky M.} and Pim-Bart Feijens and {Van Pelt}, Natascha and An Matheeussen and Sarah Hendrickx and Louis Maes and Guy Caljon and Vanessa Yardley and Susan Wyllie and Charman, {Susan A.} and Eric Chatelain",

note = "Copyright: {\textcopyright} 2023 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.",

year = "2023",

month = dec,

day = "13",

doi = "10.1126/scitranslmed.adh9902",

language = "English",

volume = "15",

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Braillard, S, Keenan, M, Breese, KJ, Heppell, J, Abbott, M, Islam, R, Shackleford, DM, Katneni, K, Crighton, E, Chen, G, Patil, R, Lee, G, White, KL, Carvalho, S , Wall, RJ, Chemi, G, Zuccotto, F, Gonzalez, S, Marco, M, Deakyne, J, Standing, D, Brunori, G, Lyon, JJ, Castañeda-Casado, P, Camino, I, Martinez Martinez, MS, Zulfiqar, B, Avery, VM, Feijens, P-B, Van Pelt, N, Matheeussen, A, Hendrickx, S, Maes, L, Caljon, G, Yardley, V, Wyllie, S, Charman, SA & Chatelain, E 2023, 'DNDI-6174 is a preclinical candidate for visceral leishmaniasis that targets the cytochrome bc1', Science Translational Medicine, vol. 15, no. 726, eadh9902. https://doi.org/10.1126/scitranslmed.adh9902

TY - JOUR

T1 - DNDI-6174 is a preclinical candidate for visceral leishmaniasis that targets the cytochrome bc1

AU - Braillard, Stéphanie

AU - Keenan, Martine

AU - Breese, Karen J.

AU - Heppell, Jacob

AU - Abbott, Michael

AU - Islam, Rafiqul

AU - Shackleford, David M.

AU - Katneni, Kasiram

AU - Crighton, Elly

AU - Chen, Gong

AU - Patil, Rahul

AU - Lee, Given

AU - White, Karen L.

AU - Carvalho, Sandra

AU - Wall, Richard J.

AU - Chemi, Giulia

AU - Zuccotto, Fabio

AU - Gonzalez, Silvia

AU - Marco, Maria

AU - Deakyne, Julianna

AU - Standing, David

AU - Brunori, Gino

AU - Lyon, Jonathan J.

AU - Castañeda-Casado, Pablo

AU - Camino, Isabel

AU - Martinez Martinez, Maria S.

AU - Zulfiqar, Bilal

AU - Avery, Vicky M.

AU - Feijens, Pim-Bart

AU - Van Pelt, Natascha

AU - Matheeussen, An

AU - Hendrickx, Sarah

AU - Maes, Louis

AU - Caljon, Guy

AU - Yardley, Vanessa

AU - Wyllie, Susan

AU - Charman, Susan A.

AU - Chatelain, Eric

PY - 2023/12/13

Y1 - 2023/12/13

N2 - 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.

AB - 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.

U2 - 10.1126/scitranslmed.adh9902

DO - 10.1126/scitranslmed.adh9902

M3 - Article

C2 - 38091406

SN - 1946-6234

VL - 15

JO - Science Translational Medicine

JF - Science Translational Medicine

IS - 726

M1 - eadh9902

ER -

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

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Projects

A Platform for Drug Target Deconvolution and Exploitation

Wellcome Centre for Anti-Infectives Research

Chemical Biology: Leveraging Phenotypic Hits Against Kinetoplastids (Strategic Grant)

Cite this