A long-duration dihydroorotate dehydrogenase inhibitor (DSM265) for prevention and treatment of malaria

Margaret A. Phillips; Julie Lotharius; Kennan Marsh; John White; Anthony Dayan; Karen L. White; Jacqueline W. Njoroge; Farah El Mazouni; Yanbin Lao; Sreekanth Kokkonda; Diana R. Tomchick; Xiaoyi Deng; Trevor Laird; Sangeeta N. Bhatia; Sandra March; Caroline L. Ng; David A. Fidock; Sergio Wittlin; Maria Lafuente-Monasterio; Francisco Javier Gamo Benito; Laura Maria Sanz Alonso; Maria Santos Martinez; Maria Belen Jimenez-Diaz; Santiago Ferrer Bazaga; Iñigo Angulo-Barturen; John N. Haselden; James Louttit; Yi Cui; Arun Sridhar; Anna-Marie Zeeman; Clemens Kocken; Robert Sauerwein; Koen Dechering; Vicky M. Avery; Sandra Duffy; Michael Delves; Robert Sinden; Andrea Ruecker; Kristina S. Wickham; Rosemary Rochford; Janet Gahagen; Lalitha Iyer; Ed Riccio; Jon Mirsalis; Ian Bathhurst; Thomas Rueckle; Xavier Ding; Brice Campo; Didier Leroy; M. John Rogers; Pradipsinh K. Rathod; Jeremy N. Burrows; Susan A. Charman

doi:10.1126/scitranslmed.aaa6645

Research ArticleMalaria

A long-duration dihydroorotate dehydrogenase inhibitor (DSM265) for prevention and treatment of malaria

Margaret A. Phillips¹,*,
Julie Lotharius²,
Kennan Marsh³,
John White⁴,
Anthony Dayan²,
Karen L. White⁵,
Jacqueline W. Njoroge¹,
Farah El Mazouni¹,
Yanbin Lao³,
Sreekanth Kokkonda⁴,
Diana R. Tomchick⁶,
Xiaoyi Deng¹,
Trevor Laird²,
Sangeeta N. Bhatia⁷,
Sandra March⁷,
Caroline L. Ng⁸,
David A. Fidock⁸,⁹,
Sergio Wittlin¹⁰,¹¹,
Maria Lafuente-Monasterio¹²,
Francisco Javier Gamo Benito¹²,
Laura Maria Sanz Alonso¹²,
Maria Santos Martinez¹²,
Maria Belen Jimenez-Diaz¹²,
Santiago Ferrer Bazaga¹²,
Iñigo Angulo-Barturen¹²,
John N. Haselden¹²,
James Louttit¹³,
Yi Cui¹³,
Arun Sridhar¹³,
Anna-Marie Zeeman¹⁴,
Clemens Kocken¹⁴,
Robert Sauerwein¹⁵,
Koen Dechering¹⁵,
Vicky M. Avery¹⁶,
Sandra Duffy¹⁶,
Michael Delves¹⁷,
Robert Sinden¹⁷,
Andrea Ruecker¹⁷,
Kristina S. Wickham¹⁸,
Rosemary Rochford¹⁸,
Janet Gahagen¹⁹,
Lalitha Iyer¹⁹,
Ed Riccio¹⁹,
Jon Mirsalis¹⁹,
Ian Bathhurst²,
Thomas Rueckle²,
Xavier Ding²,
Brice Campo²,
Didier Leroy²,
M. John Rogers²⁰,
Pradipsinh K. Rathod⁴,
Jeremy N. Burrows² and
Susan A. Charman⁵,*

¹Department of Pharmacology, University of Texas Southwestern Medical Center at Dallas, 6001 Forest Park Boulevard, Dallas, TX 75390–9041, USA.
²Medicines for Malaria Venture, 1215 Geneva, Switzerland.
³Abbvie, 1 North Waukegan Road, North Chicago, IL 60064–6104, USA.
⁴Departments of Chemistry and Global Health, University of Washington, Seattle, WA 98195, USA.
⁵Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.
⁶Department of Biophysics, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390–9041, USA.
⁷Health Sciences and Technology/Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
⁸Department of Microbiology and Immunology, Columbia University Medical Center, New York, NY 10032, USA.
⁹Division of Infectious Diseases, Department of Medicine, Columbia University Medical Center, New York, NY 10032, USA.
¹⁰Swiss Tropical and Public Health Institute, Socinstrasse 57, 4002 Basel, Switzerland.
¹¹University of Basel, 4003 Basel, Switzerland.
¹²GlaxoSmithKline (GSK), Tres Cantos Medicines Development Campus, Severo Ochoa, Madrid 28760, Spain.
¹³GSK, Park Road, Ware, Hertfordshire SG12 0DP, UK.
¹⁴Biomedical Primate Research Centre, P.O. Box 3306, 2280 GH Rijswijk, Netherlands.
¹⁵TropIQ Health Sciences, 6525 GA Nijmegen, Netherlands.
¹⁶Discovery Biology, Eskitis Institute for Drug Discovery, Griffith University, Nathan, Queensland 4111, Australia.
¹⁷Imperial College of Science Technology and Medicine, London SW7 2AY, UK.
¹⁸State University of New York Upstate Medical University, Syracuse, NY 13210, USA.
¹⁹SRI International, Menlo Park, CA 94025, USA.
²⁰National Institutes for Allergy and Infectious Diseases, 6610 Rockledge Drive, Bethesda, MD 20892, USA.

↵*Corresponding author. E-mail: margaret.phillips{at}utsouthwestern.edu (M.A.P.); susan.charman{at}monash.edu (S.A.C.)

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Science Translational Medicine 15 Jul 2015:
Vol. 7, Issue 296, pp. 296ra111
DOI: 10.1126/scitranslmed.aaa6645

Margaret A. Phillips

1Department of Pharmacology, University of Texas Southwestern Medical Center at Dallas, 6001 Forest Park Boulevard, Dallas, TX 75390–9041, USA.

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For correspondence: margaret.phillips@utsouthwestern.edu susan.charman@monash.edu

Julie Lotharius

2Medicines for Malaria Venture, 1215 Geneva, Switzerland.

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Kennan Marsh

3Abbvie, 1 North Waukegan Road, North Chicago, IL 60064–6104, USA.

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John White

4Departments of Chemistry and Global Health, University of Washington, Seattle, WA 98195, USA.

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Anthony Dayan

2Medicines for Malaria Venture, 1215 Geneva, Switzerland.

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Karen L. White

5Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.

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Jacqueline W. Njoroge

1Department of Pharmacology, University of Texas Southwestern Medical Center at Dallas, 6001 Forest Park Boulevard, Dallas, TX 75390–9041, USA.

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Farah El Mazouni

1Department of Pharmacology, University of Texas Southwestern Medical Center at Dallas, 6001 Forest Park Boulevard, Dallas, TX 75390–9041, USA.

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Yanbin Lao

3Abbvie, 1 North Waukegan Road, North Chicago, IL 60064–6104, USA.

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Sreekanth Kokkonda

4Departments of Chemistry and Global Health, University of Washington, Seattle, WA 98195, USA.

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Diana R. Tomchick

6Department of Biophysics, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390–9041, USA.

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Xiaoyi Deng

1Department of Pharmacology, University of Texas Southwestern Medical Center at Dallas, 6001 Forest Park Boulevard, Dallas, TX 75390–9041, USA.

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Trevor Laird

2Medicines for Malaria Venture, 1215 Geneva, Switzerland.

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Sangeeta N. Bhatia

7Health Sciences and Technology/Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.

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Sandra March

7Health Sciences and Technology/Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.

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Caroline L. Ng

8Department of Microbiology and Immunology, Columbia University Medical Center, New York, NY 10032, USA.

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David A. Fidock

8Department of Microbiology and Immunology, Columbia University Medical Center, New York, NY 10032, USA.

9Division of Infectious Diseases, Department of Medicine, Columbia University Medical Center, New York, NY 10032, USA.

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Sergio Wittlin

10Swiss Tropical and Public Health Institute, Socinstrasse 57, 4002 Basel, Switzerland.

11University of Basel, 4003 Basel, Switzerland.

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Maria Lafuente-Monasterio

12GlaxoSmithKline (GSK), Tres Cantos Medicines Development Campus, Severo Ochoa, Madrid 28760, Spain.

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Francisco Javier Gamo Benito

12GlaxoSmithKline (GSK), Tres Cantos Medicines Development Campus, Severo Ochoa, Madrid 28760, Spain.

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Laura Maria Sanz Alonso

12GlaxoSmithKline (GSK), Tres Cantos Medicines Development Campus, Severo Ochoa, Madrid 28760, Spain.

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Maria Santos Martinez

12GlaxoSmithKline (GSK), Tres Cantos Medicines Development Campus, Severo Ochoa, Madrid 28760, Spain.

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Maria Belen Jimenez-Diaz

12GlaxoSmithKline (GSK), Tres Cantos Medicines Development Campus, Severo Ochoa, Madrid 28760, Spain.

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Santiago Ferrer Bazaga

12GlaxoSmithKline (GSK), Tres Cantos Medicines Development Campus, Severo Ochoa, Madrid 28760, Spain.

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Iñigo Angulo-Barturen

12GlaxoSmithKline (GSK), Tres Cantos Medicines Development Campus, Severo Ochoa, Madrid 28760, Spain.

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John N. Haselden

12GlaxoSmithKline (GSK), Tres Cantos Medicines Development Campus, Severo Ochoa, Madrid 28760, Spain.

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James Louttit

13GSK, Park Road, Ware, Hertfordshire SG12 0DP, UK.

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Yi Cui

13GSK, Park Road, Ware, Hertfordshire SG12 0DP, UK.

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Arun Sridhar

13GSK, Park Road, Ware, Hertfordshire SG12 0DP, UK.

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Anna-Marie Zeeman

14Biomedical Primate Research Centre, P.O. Box 3306, 2280 GH Rijswijk, Netherlands.

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Clemens Kocken

14Biomedical Primate Research Centre, P.O. Box 3306, 2280 GH Rijswijk, Netherlands.

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Robert Sauerwein

15TropIQ Health Sciences, 6525 GA Nijmegen, Netherlands.

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Koen Dechering

15TropIQ Health Sciences, 6525 GA Nijmegen, Netherlands.

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Vicky M. Avery

16Discovery Biology, Eskitis Institute for Drug Discovery, Griffith University, Nathan, Queensland 4111, Australia.

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Sandra Duffy

16Discovery Biology, Eskitis Institute for Drug Discovery, Griffith University, Nathan, Queensland 4111, Australia.

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Michael Delves

17Imperial College of Science Technology and Medicine, London SW7 2AY, UK.

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Robert Sinden

17Imperial College of Science Technology and Medicine, London SW7 2AY, UK.

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Andrea Ruecker

17Imperial College of Science Technology and Medicine, London SW7 2AY, UK.

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Kristina S. Wickham

18State University of New York Upstate Medical University, Syracuse, NY 13210, USA.

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Rosemary Rochford

18State University of New York Upstate Medical University, Syracuse, NY 13210, USA.

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Janet Gahagen

19SRI International, Menlo Park, CA 94025, USA.

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Lalitha Iyer

19SRI International, Menlo Park, CA 94025, USA.

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Ed Riccio

19SRI International, Menlo Park, CA 94025, USA.

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Jon Mirsalis

19SRI International, Menlo Park, CA 94025, USA.

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Ian Bathhurst

2Medicines for Malaria Venture, 1215 Geneva, Switzerland.

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Thomas Rueckle

2Medicines for Malaria Venture, 1215 Geneva, Switzerland.

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Xavier Ding

2Medicines for Malaria Venture, 1215 Geneva, Switzerland.

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Brice Campo

2Medicines for Malaria Venture, 1215 Geneva, Switzerland.

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Didier Leroy

2Medicines for Malaria Venture, 1215 Geneva, Switzerland.

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M. John Rogers

20National Institutes for Allergy and Infectious Diseases, 6610 Rockledge Drive, Bethesda, MD 20892, USA.

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Pradipsinh K. Rathod

4Departments of Chemistry and Global Health, University of Washington, Seattle, WA 98195, USA.

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Jeremy N. Burrows

2Medicines for Malaria Venture, 1215 Geneva, Switzerland.

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Susan A. Charman

5Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.

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For correspondence: margaret.phillips@utsouthwestern.edu susan.charman@monash.edu

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The antimalarial drug DSM265 displays activity against blood and liver stages of Plasmodium falciparum and has a long predicted half-life in humans.

A long-duration dihydroorotate dehydrogenase inhibitor (DSM265) for prevention and treatment of malaria

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